EPA/600/8-89/002F
December 1988
Summary Review of Health Effects
Associated with Hydrogen Fluoride
and Related Compounds
Health Issue Assessment
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
For sale by the Superintendent of Documents, U.S. Government
Printing Office, Washington, D.C. 20402
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Disclaimer
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement or
recommendation for use.
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Preface
The Office of Health and Environmental Assessment has prepared this
health assessment to serve as.a source document for use by the Office of Air
Quality Planning and Standards to support decision making regarding possible
regulation of hydrogen fluoride as a hazardous air pollutant.
In the development of this assessment document, the scientific literature
through January 1987 has been inventoried, key studies have been evaluated,
and summary/conclusions have been prepared so that the chemical's toxicity
and related characteristics are qualitatively identified. Observed effect levels
and other measures of dose-response relationships are discussed, where
appropriate, so that the nature of the adverse health responses is placed in
perspective with observed environmental levels.
Any information regarding sources, emissions, ambient air concentrations,
and public exposure has been included only to give the reader a preliminary
indication of the potential presence of this substance in the ambient air. While
the available exposure information is presented as accurately as possible, it is
acknowledged to be limited and dependent in some instances on assumption
rather than specific data. This exposure information is not intended, nor should
it be used, to support any conclusions regarding risk to public health.
If a review of the health information indicates that the Agency should
consider regulatory action for this substance, a considerable effort will be
undertaken to obtain appropriate information regarding sources, emissions,
and ambient air concentrations. Such data will provide additional information
for drawing regulatory conclusions regarding the extent and significance of
public exposure to this substance.
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Table of Contents
Preface jjj
Tables \ ' vj
Authors and Contributors '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'. vii
1. Summary and Conclusions 1-1
2. Introduction 2-1
3. Air Quality and Environmental Fate , 3-1
3.1 Sources 3-1
3.2 Distribution and Fate 3.3
3.3 Ambient Levels 3-4
3.4 Exposure 3.5
4. Pharmacokinetics 4.1
4.1 Absorption " 4_1
4.2 Retention and Distribution 4-2
4.3 Excretion 4,3
5. Mutagenicity and Garcinogenicity 5-1
5.1 Mutagenicity '.'.'.'.'.'.'.'. 5-1
5.2 Carcinogenicity 5-2
6. Developmental and Reproductive Toxicity 6-1
7. Other Toxic Effects 7_1
7.1 Acute Toxicity ':'.'.'.'.'' 7-1
7.2 Chronic Toxicity '.'.'.'.';'.'.'.'.'.'. 7-4
7.3 Biochemical Effects '.'.'.'.'.'. 7-6
8. Beneficial Effects 8-1
9. References g_1
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List of Tables
No.
1-1 Summary of human fluoride intake from various sources :
1-2 Summary of effects on humans of various levels of fluoride
intake
1-3 Summary of official standards and human toxicity limits for
airborne hydrogen fluoride, fluorine, and fluorides ....
2-1 Physical and chemical properties of hydrogen fluoride .. .
2-2 Physical properties of aqueous seventy percent
hydrogen fluoride • • • -,;.;
2-3 U.S. hydrogen fluoride consumption . .'.''
2-4 U.S. fluorine sources and consumption
3-1 Fluoride emissions to the atmosphere by industrial
sources in the United States
7-1 Summary of lethal concentration (LC) estimates for HF.
inhalation
1-5
1-7
2-2
2-8
2-9
3-2
VI
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Authors arid Contributors
The author of this document is Kathleen M. Thiessen, Ph.D Chemical/1'
Effects Information Branch, Information Research and Analysis Division Oak
Ridge National Laboratory,,P.O. Box X; Oak Ridge, Tennessee 37831,.' '
The U.S. EPA project manager for this document is David E Weil Ph D
Environmental Criteria and Assessment Office, Office of Health and
Environmental Assessment, MD-52, Research Triangle Park, North Carolina;
, „ PEER REVIEWERS
Earlier drafts of this document were reviewed by the following individuals*:.
Dr. John Morris
University of Connecticut
Storrs, CT ' " ; •'
Dr. John Drury ' •
Oak Ridge, TN ' '
Dr. Frank Smith
Rochester, NY
"Peer reviewers were selected on the basis of their recognized expertise
and contributions to the scientific literature on hydrogen fluoride and
related compounds.
VII
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1. Summary and Conclusions
Anhydrous hydrogen fluoride (HF) is a colorless, fuming corrosive liquid
or gas at room temperature and is one of the strongest acids known; aqueous
HF, or hydrofluoric acid, is) a weak acid. Hydrogen fluoride is highly reactive
with a number of materials. Some HF is produced naturally by volcanic
activity; commercial production is by the reaction of su If uric acid with
fluorspar. Hydrogen fluoride is probably the most important of the many
fluorine-containing compounds, because it is used in the production of most of
the other fluorine compounds.
The major uses of hydrogen fluoride are in the aluminum and
f uorpcarbon industries. Steel production is a major user of solid inorganic
fluoride (F) in the form of fluorspar. Hydrogen fluoride and other inorganic
fluoride compounds are also important for a number of other uses (eg
uranium processing, petroleum alkylation, manufacturing fluoride salts and
metal pickling and fluxing operations). Total HF and fluorspar consumption has
decreased since 1974, and an increasing proportion of the HF and fluorspar
used in the United States is imported.
The major natural sources of airborne HF and other airborne fluorides are
volcanic activity, ocean spray, and dust from the weathering of fluoride-
containing rocks or soils. Anthropogenic sources include emissions from
industrial operations consuming HF or fluorspar and from the combustion of
coal for power; these sources may contribute as much as 150 thousand metric
tons of airborne fluoride per year in the United States and 3.6 million metric
tons per year worldwide. Twenty to forty percent of industrial fluoride
emissions are in gaseous form, the rest are particulate. Many of the gaseous
fluorides, including HF, are hydrolyzed and dispersed in the atmosphere-
particulate fluorides generally settle to the ground as dusts. The major route'
for removal of airborne fluoride is atmospheric precipitation, and most of the
fluoride in precipitation is thought to be of anthropogenic origin.
At least 300,000 workers in the United States may have potential
exposure to HF or to other inorganic fluorides. Occupational HF and fluoride
(as F) exposure limits are set at 2.5 mg/ms (3 ppm HF) for an 8-hour working
day. A maximum of 10 to 25 mg fluoride per day could be inhaled by a worker
under these exposure limits. Exposure of the general public to airborne
fluorides, including HF, is greatest in the vicinity of point sources such as
factories; average total fluoride concentrations near industrial operations in the
United States and Canada are normally below 8.2 tig/ms. People living in
highly polluted industrial areas probably inhale at most 0.2 mg of fluoride per
day. Fluoride intake from food and water is probably about 2 to 3 mg/day
(normal range, 0.25 to 5.4 mg/day) per person, depending on individual diet
and whether or not the local water supply is fluoridated. Cigarette smokers
may inhale as much as 0.8 mg fluoride per day. Fluoride intake may also
occur from other sources such as fluoridated dentifrices. Most of the toxic
effects of hydrogen fluoride to humans are attributable to the fluoride ion and
fluoride exposure from all sources must be assessed in the determination of
the health effects of HF or fluoride on the human population.
1-1
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Absorption of fluoride in mammals is dependent primarily on the solubility
of the specific compound: NaF is readily absorbed in the gastrointestinal tract,
CaF2 much less so. Hydrogen fluoride is rapidly absorbed via the lungs, skin,
or gastrointestinal tract. Not all paniculate fluorides are actually deposited in or
absorbed from the respiratory tract; some are exhaled without ever being
deposited on the surface of the respiratory tract. As much as one half of
absorbed fluoride may be retained in the human body, most of it in the
skeleton. The plasma concentration of ionic fluoride is directly relate.d to the
fluoride content of the drinking water and is normally in the range of 10 to 20
ng/L Clearance from the blood is by uptake into bones or teeth (especially in
children), where it replaces hydroxyl ions in the apatite lattice, and by
excretion via the kidneys. Urinary excretion is the main route of removal of
fluoride from the body, and fluoride levels in urine are correlated with fluoride
intake. People with renal dysfunction will excrete less than normal amounts of
fluoride; Because of the increased retention of fluoride, these people are at a
higher risk for toxic effects caused by fluoride.
Some studies have suggested that HF and NaF are genotoxic in plants,
Drosophila, or mammals, primarily by causing chromosome breakage. The
fluoride concentrations used to induce genotoxic effects in many in vivo
experiments are several hundred to several thousand times higher than the
blood fluoride levels expected in humans. Epidemiological studies have not
provided evidence for an association between fluoride in drinking water and an
increased risk of cancer mortality. Increased rates of cancer have been
reported for workers in several occupations involving possible fluoride
exposure; however, all these situations involved mixed exposures to several
chemicals, and fluoride could not be specifically implicated as the cause of the
cancers. No animal bioassays have been reported on the potential
carcinogenicity of inhaled fluorides, and tests of sodium fluoride administered
orally to mice have been inconclusive. The available evidence is thought to be
inadequate to support or refute a carcinogenic potential for inhalation exposure
to fluorides. The United States Environmental Protection Agency has not
classified fluoride or hydrogen fluoride with respect to potential
carcinogenicity. . . .
Fluoride can cross the placenta and be deposited in the calcified tissues
of the fetus; fetal exposure is proportional to maternal exposure. High levels of
fluoride have caused impaired reproduction or malformation of fetal bones and
teeth in some mammalian species, but no adverse effects on human reproduc-
tion or fetal development are expected at fluoride levels likely to be
encountered by humans.
The major developmental risk to humans from fluoride is dental mottling
or fluorosis. This occurs in individuals receiving excess fluoride (usually in the
drinking water) during the period of tooth mineralization (prior to birth for
deciduous teeth and up to age 12 for the last of the permanent teeth). Mild to
moderate dental fluorosis (from water fluoride levels up to 4 mg/L) is
considered a cosmetic effect rather than a health effect.
Acute exposure to gaseous fluoride is rare in a nonoccupational setting.
Hydrogen fluoride and fluorine are extremely toxic, with IDLH ("immediately
dangerous to life and health") levels of 16.4 and 50 mg/m3 (20 and 25 ppm),
respectively. Both gases can cause- severe respiratory damage or skin burns
on contact. Aqueous hydrofluoric acid also causes severe burns. The skin
burns and respiratory damage caused by hydrogen fluoride are the only toxic
effects of hydrogen fluoride which are not attributable solely to the action of
the fluoride ion, and -systemic fluoride poisoning usually does occur from HF
absorbed via the lungs or the skin. Ingested fluorides also cause systemic
1-2
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fluoride poisoning. Symptoms of acute fluoride poisoning include convulsions
and cardiac arrhythmias, and death is usually from cardiac or respiratory
failure and occurs within 24 hours. An acute dose of 8 to 16 mg fluoride per kg
body weight can be safely tolerated by humans; a dose of 32 to 64 mg/kg is
lethal. No acute effects of hydrogen fluoride 6r other inorganic fluorides are
noticed at air fluoride levels of 2.6 mg/m3.
The bones and teeth are the tissues most sensitive to long-term fluoride
intake. Chronic fluoride exposure to 0.1 to 0.35 mg/kg/day during childhood
can result jn dental fluorosis or mottling. Skeletal fluorosis requires a higher
fluoride intake (0.2 to 1.0 mg/kg/day or more) over many more years. The
earliest observable effect of fluoride deposition in the skeleton is an increased
opacity of the bone to X-rays, known as osteosclerosis, which is first
noticeable when the fluoride level reaches 5000 to 6000 mg/kg of dry, fat-free
bone. Skeletal fluorosis increases in severity with increased fluoride intake and
increased time. Crippling fluorosis is characterized by pain, stiffness, irregular
bone growth, and calcification of ligaments and tendons; this occurs only when
occupational fluoride exposure has been very high (resulting in an intake of 20
to 80 mg/day for 10 to 20 years) or when drinking water contains 10 to 40
mg/L fluoride. Other effects of chronic fluoride exposure on humans have been
reported, including hypersensitivity and dermatological reactions, but none has
been convincingly established. The United States Environmental Protection
Agency (1986) has established an oral Reference Dose (RfD) of 0.06
mg/kg/day for children (corresponding to a water fluoride level of 1 mg/L)
which is adequate to prevent dental and skeletal fluorosis. An inhalation RfD is
not available.
Fluoride toxicity involves at least four major effects: inhibition of various
enzymes, hypocalcemia, cardiovascular collapse, and damage to specific
organs such as the brain and the kidneys. The major chronic effects of fluo-
ride may be caused by the action of the fluoride ion on various enzymes and
thereby on metabolic pathways. Many of the acute toxic effects of fluoride,
such as the cardiac arrhythmias, may be caused by hypocalcemia, and most
methods of treatment of acute fluoride poisoning or HF burns include
immediate replacement of calcium.
It is generally accepted that fluoride has a significant cariostatic effect on
human teeth, particularly for individuals who receive it during childhood.
Fluoride acts systemically in ,the formation of teeth by being built into the
crystal structure of the enamel, making it harder and more resistant to decay;
fluoride also acts topically on erupted teeth by promoting remineralization and
by inhibiting acid production by bacteria. In many communities, fluoride is
administered to the population via the water supply, typically at a level of 1
ppm fluoride, depending on the average local temperature. A few reports
suggest that at least some of the decline in tooth decay attributed to
fluoridated water may in fact be due to other causes, such as changes in
immune status, changes in dietary patterns, and use of topical fluorides.
The use of fluoride has also been suggested as a means of preventing or
treating osteoporosis, or premature bone loss. Some evidence exists which
indicates that people living in an area with a high natural level of fluoride in the
water (4 to 8 mg/L) have a lower incidence of osteoporosis, but medical use of
high fluoride doses is still under investigation. Fluoridated water may also be
correlated with a lower incidence of cardiovascular disease. The beneficial
effects and the adverse effects of fluoride must be weighed in determining the
optimal dose for humans, and in particular for the optimal fluoride level to be
maintained in public water supplies.
1-3
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In summary, most of the toxic effects of hydrogen fluoride are attributable
to the effects of fluoride ion. Acute inhalation of HF or skin contact with HF or
hydrofluoric acid results in respiratory damage or skin burns, as well as
systemic fluoride effects. Average air fluoride concentrations near industrial
operations are usually less than 8.2 iig/mS and exposure of the general public
to airborne fluorides is normally less than 0.2 mg/day per person in industrial
areas and even less in rural areas. For most people, exposure to airborne
fluorides is considerably less than exposure to fluoride from other sources
such as food and water; nevertheless exposure to fluoride from all sources
must be assessed in the accurate determination of the health effects on the
human population. Most people probably ingest 0.25 to 5.4 mg fluoride per
day, depending on individual diet and the fluoride content of local water
supplies; smokers may inhale another 0.8 mg fluoride per day. Table 1-1
contains a summary of human fluoride intake from various sources.
Some fluoride intake, about 0.06 mg/kg/day (1.2 mg/day in a 20-kg child
or 4.2 mg/day in a 70-kg adult) has a beneficial effect in the prevention of
dental caries, particularly for those receiving it during childhood. A fluoride
intake of 0.2 to 0.35 mg/kg/day (4 to 7 mg/day for a child) during childhood
commonly causes dental fluorosis. Long-term fluoride intake of 0.2 to 1.0
mg/kg/day (14 to 70 mg/day for an adult) or more will result in severe skeletal
fluorosis. An acute fluoride intake of 8 to 16 mg/kg can be safely tolerated by
humans; a dose of 32 to 64 mg/kg is lethal. Table 1-2 summarizes the effects
on humans of various levels of fluoride intake, and Table 1-3 summarizes the
existing official standards and human toxicity limits for airborne hydrogen
fluoride, fluorine, and inorganic compounds of fluoride.
1-4
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Table 1-2. Summary of Effects on Humans of Various Levels of
Fluoride Intake
Description
Averaging Time Intake or Exposure
4000-5000 ppm fluoride in
bones •
NOAEL (oral), RfD (oral)
cariostatic effect, very mild
dental fluorosis in about 1 in 5
people
LOAEL (oral) dental mottling,
mild dental fluorosis
dental fluorosis common,
sometimes severe
6000 ppm fluoride in bone,
osteosclerosis, skeletal
fluorosis
crippling skeletal fluorosis
no effect (oral)
lethal (oral)
60 years
0-12 years of age
0-12 years of age
0-12 years of age
2-35 years,
average of 8 years
20 years;
> 2 years, dose
dependant
acute
acute
0.02-0.04 mg/kg/day
1 mg/L (water)
0.06 mg/kg/day
1 mg/L (water)
0.11 mg/kg/day
2 mg/L (water)
0.2-0.35 mg/kg/day
>4 mg/L (water)
0.2-1.0 mg/kg/day
8 mg/L (water)
0.14-3.43 mg/m3 (air)
0.2-10+ mg/kg/day
> 1 0 mg/L (water)
12-26 mg/m3 (air)
8-16 mg/kg
32-64 mg"/kg
a The information above is from human data. The estimates of fluoride intake and
fluoride exposure levels are those reported in the cited publications; they were
not derived by use of conversion factors. If an air concentration is not given in
the table, assume that no information was found associating that effect with a
particular airborne fluoride concentration.
Abbreviations: NOAEL - No Observed Adverse Effect Level
RfD - Reference Dose
LOAEL - Lowest Observed Adverse Effect Level
Sources: Heifetz and Horowitz, 1986; United States Environmental Protection
Agency, 1986; Federal Register, I985b; World Health Organization,
1984; Hayes, 1982; Drury et al., 1980.
1-6
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Table 1-3. Summary of Official Standards and Human Toxicity Limits for
Airborne Hydrogen Fluoride, Fluorine, and Fluorides
Standard or Effect ,
Detection by smell
ACGIH - TWA (8-hr)
- STEL (15-min)
NIOSH - TWA (8-hr)
- STEL (15-min)
OSHA - TWA (8-hr) ,
No acute effect
Irritation (>,10 min)
(<1C> min) .
IDLH , . , .
Breathing impossible
Lethal (LCLO, 5 min)
Lethal (LC10o. 60 min)
Hydrogen
Fluoride
mg/m3
0.0343
2.5
(ceiling)
na
2.5
5.0
2.5C
2.6 (<8 h)
13
26
16.4d
na
41-205'
877'
Fluorine ,.
mg/m3
, 0.28b
2
4
na
na
0.2
15
na
25-40
5Qe
75
na
na • ' -
Fluorides
as F •".'
mg/m3
na
2.5
na
2.5
na
2.5
. na .
na
na
500
, na
na
na
.Sources
-:.'.. B
' A
A
• F, G
F
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, .. E
E
, ' ' E
H
E
- D
E
na - data not available.
aGiven as 0.042 ppm in the cited publication. '
bGiven as 0.14 ppm in the cited publication. ...
°Given as .3 ppm .in the cited publication. .
dGiven as 20 ppm in the cited publication.
6Given as 25 ppm in the cited publication.
'See Table 7-1 for other LC values.
Abbreviations: ACGIH.- American Conference of Governmental Industrial Hygienists; IDLH
- Immediately Dangerous to Life and Health; LC^o - lowest lethal concentration for the
exposed population (estimated); LC100- lethal concentration for 100 percent of the exposed
population (estimated); NIOSH - National Institute for Occupational Safety and Health;
OSHA - Occupational Safety and ;Health Administration; STEL - Short Term Exposure
Limit; TWA - Time Weighted Average.... •
Sources: A) American Conference of Governmental Industrial Hygienists, 1986.
B) Amoore and Hautala, 1983.
C) Code of Federal Regulations, 1985.
D) Halton et al., 1984.
E) Just and Emler, 1984.
F) National Institute for Occupational Safety and Health, 1976; 1975.
G) National Institute for Occupational Safety and Health, 1976.
H) Sittig, 1985.
1-7
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2. Introduction
This report is intended to provide a brief review of the available
information on the potential health effects associated with exposure to
hydrogen fluoride and related compounds. Emphasis is placed on the potential
health effects on the general public from exposure to ambient airborne
concentrations. Sources, distribution, fate, and ambient levels of hydrogen
fluoride and other inorganic fluorides are reviewed. Because most of the toxic
effects of hydrogen fluoride are attributable to the fluoride ion, data concerning
the pharmacokinetics, mutagenicity, carcinogenicity, teratogenicity, acute and
chronic toxicity, and beneficial effects of both hydrogen fluoride and fluoride in
general are discussed.
Fluorine (F) is the 13th most abundant element (Hodge and Smith, 1972).
It is the most electronegative of all the elements, combining with almost all
other elements (Stokinger, 1981); elemental fluorine is therefore not found in
nature. Most naturally occurring fluorine is in the form of minerals, primarily
fluorspar (fluorite, CaF2), phosphate rock (fluorapatite, CaF2«3Ca(P04)2), and
natural cryolite (Na3AIF6; Levenson et al., 1982). Hydrogen fluoride is probably
the most important of the numerous fluorine compounds, as it is used in the
production of elemental fluorine (F2) and in the synthesis of many other
fluorine compounds, both organic and inorganic. Some HF is produced
naturally by volcanic activity (Stokinger, 1981); most commercially used HF is
produced by the reaction of sulfuric acid (H2SO4) with fluorspar to give HF and
calcium sulfate (gypsum, CaSO4; Levenson et al., 1982). Hydrogen fluoride is
also produced as a by-product in industries using phosphate rock or cryolite.
Anhydrous hydrogen fluoride (HF) is a colorless, fuming, corrosive liquid
or gas at room temperatures (boiling point, 19.54°C). Hydrogen fluoride is
readily soluble in water and in a number of other solvents; aqueous HF is
usually referred to as hydrofluoric acid. Anhydrous HF is one of the most
acidic substances known, with a Hammet acidity function of -10.98 (Windholz
et al., 1983); in aqueous solution, HF is a weak acid (Ka = 6.46 x 10-4
moles/liter). Hydrogen fluoride will attack glass, concrete, and certain metals
especially those containing silica (Weiss, 1980). Anhydrous HF actively
dehydrates many organic materials, charring wood and paper on contact (Gall
1980). Although not flammable itself, HF in contact with some metals may
generate flammable hydrogen gas (Weiss, 1980). Polymerization of HF
molecules due to hydrogen bonding occurs in the solid, liquid, and gaseous
states (Gall, 1980). The strength of the hydrogen-fluorine bond, the hydrogen
bonding and polymeric association of HF molecules, the strong acidity of
anhydrous HF in contrast to its weak acidity in aqueous solution, and the
absence of oxidation states of fluorine other than -1 are the most significant
features of the chemistry of hydrogen fluoride (see Gall, 1980, for a review of
hydrogen fluoride chemistry). Important chemical and physical properties of
hydrogen fluoride and aqueous 70 percent hydrogen fluoride are summarized
in Tables 2-1 and 2-2, respectively.
Hydrogen fluoride and hydrofluoric acid are used in a number of
industries; since the 1930's, the two major uses of HF have been in aluminum
2-1
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Table 2-2. Physical Properties of Aqueous Seventy
• Percent Hydrogen Fluoride •.... • - s;.
. Boiling, Point:
Freezing Point:
Vapor Pressure:''
Density:
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150 mm Hg (20 kPa, 2.9 psia) at 25RC. ".^
1.22 g/cm3 at 25 °C
Source: Gall (1980) :
manufacture and fluorocarbon production (Levenson et al., 1982; Gall, 1980;
Stuewe, 1958). Other important uses for HF include uranium processing,
petroleum alkylation, stainless steel pickling, etching of glass and
semiconductor components, and the production of synthetic cryolite, fluorine
gas, fluoride salts, fluorine-containing plastics, and special metals. End uses of
other fluoride compounds include water fluoridation (for prevention of dental
caries), ore flotation, wood preservation, electroplating, and chemical cleaning.
The consumption of hydrogen fluoride by the major U.S. industries is given in
Table 2-3 for the years 1957 (near the beginning of rapid growth in HF usage),
1974 (at the peak of HF usage in the aluminum and fluorocarbon industries),
and 1981 (more typical of recent HF consumption following the effects of the
economic recession on aluminum production and of environmental legislation
on fluorocarbon production). Total HF consumption in the U.S. was between
320 and 340 thousand metric tons from 1975 to 1981 (Levenson et al., 1982);
HF consumption was 277 thousand metric tons in 1985 and is expected to
reach 318 thousand metric tons) by 1989 (Chemical Marketing Reporter,
1986). U. S. fluorspar and hydrogen fluoride production have been generally
decreasing since 1974 (Table 2-4). The decrease in HF production has been
larger than the decrease in HF consumption; imports of HF to the U. S. have
been showing a corresponding increase. Mexico and Canada are the principal
sources of imported HF. Most of the fluorspar used in the U. S. is also
imported, primarily from Mexico and the Republic of South Africa (Levenson et
al., 1982). About fifty to seventy percent of U. S. fluorspar consumption is for
HF production; most of the rest of the fluorspar goes directly to steel
production (Table 2-4), where it is used to increase the fluidity of the slag. The
steel industry, and therefore the consumption of fluorspar by the steel
industry, is highly dependent on economic factors. Steel-making processes
have also been changing, from mostly open hearth production to mostly basic
oxygen or electric processes, and this also affects fluorspar consumption by
the industry (Levenson et al., 1982).
Total industrial emission of soluble fluoride in the United States (around
1964-1970) was an estimated 140 to 150 thousand metric tons per year (Smith
and Hodge, 1979; Krook and Maylin, 1979a), and in Canada (1972) about 14
thousand metric tons per year (Krook and Maylin, 1979a). The emission rate
for hydrogen fluoride in the U.S. in 1980 from HF manufacture, aluminum
production, phosphate processing, and coal combustion was an estimated
81.5 thousand metric tons per year (Misenheimer et al., 1985). Volcanic and
fumarolic activity (throughout the world) is estimated to contribute up to 7.3
million metric tons of fluoride per year to the atmosphere (Bartels, 1972;
Carpenter, 1969).
Several comprehensive reviews exist on occupational exposure to and
risks from fluorides or HF, the effects of HF or fluorides on plants and animals,
and health and environmental effects of fluorides (see for instance Smith,
1986b; World Health Organization, 1984; Jahr, 1983; Smith et al., 1982; van
2-6
-------
Haut and Krause, 1982; Dairy et al., 1980; Safe Drinking Water Committee,
1980; 1977; Smith and Hodge, 1979; Hodge and Smith, 1977; National
Institute for Occupational Safety and Health, 1976; 1975; National Research
Council, 1974; 1971; Hodge and Smith, 1965). This report seeks to
concentrate on the effects of human health that can be expected from ambient
airborne concentrations, of hydrogen fluoride and other fluorides.
2-7
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enson et al., 1 982; SRI I
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-------
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3. Air Quality and Environmental Fate
3.1. Sources
The only known natural source of hydrogen fluoride is volcanic activity
(Stokinger, 1981). Masaya Volcano in Nicaragua, for instance, emits 5 metric
tons of HF per day during its active degassing phase (Baxter et al., 1982). The
kinds and amounts of gases emitted vary between volcanoes, and in most
cases HF is not the major component of the emissions. A number of other
inorganic fluoride compounds are also present in volcanic emissions, including
F2, NH4F, KF, NaF, CaF2, MgF2, SiF4, (NH4)2SiF6, Na2SiF6, K2SiF6, and KBF4
(Smith and Hodge, 1979); trace amounts of a few fluorine-containing organic
compounds have also been identified in the emissions. Fluorine or fluoride
compounds have been found in the emissions of volcanoes in Alaska, Hawaii,
Central America, Iceland, New Zealand, the Azores, the Canary Islands,
Martinique, and several places in Europe and Asia. Total fluoride
concentrations in fumarole condensates of several Central American volcanoes
range from <0.1 to 200 mg/kg (Smith and Hodge, 1979); the total worldwide
contribution of fluoride to the atmosphere by volcanic and fumarolic activity
has been estimated to be 1 million metric tons of fluoride per year (Carpenter,
1969; Bartels, 1972, estimates it to be 7.3 million metric tons per year).
Natural sources of other airborne fluoride compounds include ocean spray
and dust from the weathering of fluoride-containing rocks or soils (Smith and
Hodge, 1979). Fluoride concentrations in rocks range from 80 to 4700 mg/kg
and in soils from traces to 7070 mg/kg with means around 200 to 300 mg/kg.
Fresh water sources in North America contain 0 to 16 mg/L fluoride,
depending on the minerals the water comes in contact with and several other
factors such as temperature and pH (Smith and Hodge, 1979). Airborne dust
collected at sea is thought to derive from continental or volcanic rocks, since
its fluoride content, which ranges from 330 to 875 mg/kg, approximates that of
crustal rocks. Seawater itself typically contains 1.2 to 1.4 mg/L dissolved
fluoride, about half of which is thought to be present as MgF (Carpenter,
1969). Essentially all of the fluoride-containing dust is thought to remain in a
particulate form, eventually settling out on land or over water, where it
sediments (Carpenter, 1969). Sea salt may contribute a variable amount of
dissolved fluoride to the air (see Carpenter, 1969; Mahadevan et al., 1986), but
it does not appear to be a major source of airborne fluoride (Barnard and
Nordstrom, 1982).
Anthropogenic sources of hydrogen fluoride and other fluorides include
coal-burning facilities and industries which produce or consume hydrogen
fluoride or other fluorides, especially the steel, aluminum, and phosphate rock
(fertilizer) industries (Table 3-1). Total soluble fluoride emissions from
industrial sources were 140 to 150 thousand metric tons per year in the U. S.
around 1970 (Krook and Maylin, 1979a; Smith and Hodge, 1979); the U. S.
emission rate for hydrogen fluoride from HF manufacture, aluminum
production, phosphate processing, and coal combustion was an estimated
81.5 thousand metric tons per year in 1980 (Misenheimer et al., 1985; this
3-1
-------
Table 3-1.
Fluoride Emissions to the Atmosphere by Industrial Sources in
the United States3
Source
Coal combustion for power
Steel
Phosphate rock processing
Aluminum processing
HF production
Miscellaneous sources
Total
Sources: Boscak (1 978);
Total Fluoride
(1968-1970)
24.1
58.6
19.3
14.7
0.6
32.9
150.2
Krook and Maylin (1 979a); Smith and I
HF
(1980)
63.2 .
b •
6:2
12.1
0.02
': b'
81.5
Hodge (1979);
Misenheimer et al. (1985).
aData given in thousands of metric tons per year. " •
bData not available. • ". ''
report assumes that all the fluorine emitted from coal combustion is in the
form of HF but admits that this has not yet been demonstrated). Hydrogen
fluoride production is a minor source of fluoride emission when compared with
the aluminum, phosphate, or steel industries, or with coal combustion (Table
3-1). Steel production is one of the major sources of fluoride emissions
(mostly particulate fluorides from the fluorspar in the flux), although fluorides
are not the major emission from steel plants (United States Environmental
Protection Agency, 1977). Coal combustion is probably the other major source
of fluoride emission (various coals contain up to 141 trig/kg fluorine with a
mean of 74 mg/kg; Misenheimer et al., 1985), although again, HF (or other
fluoride compounds) is not the major emission from coal burning facilities.
Total worldwide fluoride (soluble and particulate) emissions from industrial
sources were estimated to have been 3.6 million metric tons in 1972 (Barnard
and Nordstrom, 1982).
Emission factors for HF, particulate fluorides, or SiF4 are available for coal
combustion, HF manufacture, frit manufacturing, phosphate processing, and
the various methods and steps of aluminum and steel production
(Misenheimer et al., 1985; United States Environmental Protection Agency,
1984; 1983; 1980a; 1980b; 1977). These give an emission' rate for a pollutant
in terms of amount of a substance consumed or produced. For instance, the
emission factor for HF production in the absence of any emission controls is
12.5 kg HF emitted per metric ton of HF produced (25.0. Ibs/ton; Misenheimer
et al., 1985); when emission control (a caustic scrubber) is used, the emission
factor is 0.1 kg/metric ton of acid produced (0.2 Ibs/ton). By using a production
figure for HF of 193 thousand metric tons per'year (the amount of/HF
produced and withdrawn from the system in the United States in 1980;
Levenson et al., 1982; see Table 2-4, p. 2-9) together with the emission factors
given above, estimates of 2.4 and 0.02 thousand metric tons HF per year are
obtained for uncontrolled and controlled emissions, respectively, from HF
production in the United States. Actual HF emissions from HF production in
1980 are in fact estimated to be 0.02 thousand metric tons (21.3 tons;
Misenheimer et al., 1985; see Table 3-1). Actual amounts of U. S. fluoride
(including HF) emissions have been changing in recent years due to changes
3-2
-------
in industrial methodology (from primarily open hearth to basic oxygen
processes in steel production, for instance), increasing efficiency of emission
controls, and various economic considerations.. The steel and aluminum
industries in particular arerhighly dependent dn economic 'conditions in terms
of total production; it is also becoming economically desirable to recycle as
much fluorine or fluoride as possible in the aluminum and petroleum alkylation
industries (Levenson et al., 1982). j
Gaseous fluorides commonly make up |20 to 40 percent of industrial
fluoride emissions (Barnard and Nordstrom, 1982; both Alary et al., 1981, and
Krook and Maylin, 1979a, give around 50 percent for specific factories). Most
of these gaseous fluorides are in the form of HF or SiF4, but H2SiF6, BF3, and
F2 may also be emitted from the .glass and phosphate industries (Smith and
Hodge, 1979) and UF6 from uranium processing facilities (Bostick et al., 1985).
Common particulate fluorides released from industrial sources include
Na3AIF6, AIF3, Na5A13F14, CaF2, NaF, Na2£iF6, PbF2, and Ca10(PQ4)6F2
(Smith and Hodge, 1979). j
Hydrogen fluoride is found in the stratosphere (about 12 km altitude) at a
latitude-dependent column amount of about 1.4 to 5.4 x 1014 molecules per
square cm (Mankin and Coffey, 1983). Thijs HF is almost entirely from
decomposition of chlorofluoromethanes of anthropogenic origin, and seems to
be increasing at a rate of about 12 percent p^r year. Unlike chlorine, fluorine
does not react with ozone, so that HF in thei stratosphere is stable. The HF
gradually diffuses to the troposphere, where it is rained out (Mankin and
Coffey, 1983). .'•._•••.'_ I
- ,- • j
3.2 Distribution and Fate
The major gaseous fluorides released to'the environment, HF and SiF4,
are both readily hydrolyzed and dispersed in the atmosphere (Barnard and
Nordstrom, 1982). Anhydrous HF combines with water vapor in the air to form
aqueous hydrofluoric acid (National Researc^ Council, 1971). Several volatile
inorganic fluorides, including SF4, S2F2, and (fluorine gas and other halogen
fluorides, as well as SiF4, give rise to hydrolysis products which are less
volatile and which are eventually removed from the atmosphere by
condensation or hucleation processes (Drury et al., ,1980; see National
Research pouncil, 1971, for a discussion| of fluoride chemistry in the
atmosphere). Uranium hexafluoride, UF6, also hydrolyzes to form a less
volatile product/UO2F2, plus HF (Bostick etjal., 1985). Uranium compounds
pose a greater health hazard in terms of their radioactivity than their fluoride
content; for that reason stringent controls, are (practiced and emissions of UF6
and related compounds :are normally very small (Drury et al., 1980; see also
Bostick et al., 1985), although accidental releases do occur (see for instance
Murphy, 1986).. .'-''''.. |
Most particulate fluorides of industrial origin are stable compounds and do
not hydrolyze (Drury et al., 1980); most of these settle to the ground as dusts.
The availability of the fluoride in these compounds to plants or to herbivores is
dependent on the solubility of, the compounds, which varies between
compounds and also between solvents. NaF is readily soluble in water, while
CaF2 is essentially insoluble. Fluorapatite is insoluble in water, but it is at least
somewhat soluble in the gastrointestinal tracts of animals which ingest it as
dust on their forage (National Research Council, 1971).
Atmospheric precipitation is probably the main route for removal of
airborne fluoride compounds (Mahadevan et a ., 1986; Barnard and Nordstrom,
1982). Total inorganic fluoride concentrations! (including all F from hydrogen
fluoride or other fluoride compounds) up to 14;.1 mg/L, depending on proximity
3-3
-------
to industrial activities, have been measured in rain- and snowfall (Smith and
Hodge, 1979). Mahadevan et al. (1986) found an average fluoride
concentration in precipitation of 3 to 5 ng/L (range, 1 to 12 ng/L) for
background (nonindustrialized) sites in India and 20 ng/L or more for industrial
areas. The calculated contribution of soil fluoride to precipitation was 0.6 ng/L
A variable amount of fluoride contribution from sea salt was demonstrated for
coastal and marine areas; the total fluoride in the precipitation in these areas
was still much less than for the industrial areas.
Barnard and Nordstrom (1982) obtained a mean background fluoride
concentration in precipitation of 8.1 ng/L (range, 0 to 18 ng/L) for nonindustrial
sites in the eastern United States. They were unable to demonstrate a fluoride
contribution from sea salt. From their estimate of 3.6 million metric tons of
fluoride released to the atmosphere from industrial sources (worldwide) in
1972, they calculate a fluoride concentration in rainfall of 7.6 ng/L. If maximum
fluoride contributions from dust (1 ng/L) and volcanic activity (2 to 3 ng/L) are
added to that figure, a maximum rainfall fluoride concentration of 11.6 yg/L is
obtained. Because there is no volcanic activity in the eastern United States
(and therefore the maximum expected concentration of fluoride in the rainfall
is 8.6 pg/L), Barnard and Nordstrom conclude that most fluoride in
atmospheric precipitation is of anthropogenic origin. Fluoride in precipitation
eventually ends up in the soil and the ground water.
3.3. Ambient Levels
Ambient air concentrations of total inorganic fluoride (including fluoride
from HF and any other fluoride compounds) or of gaseous and particulate
fluorides have been measured at various industrial and nonindustrial sites.
Similar measurements for hydrogen fluoride alone are generally not available.
In rural air, away from any industrial sources of fluoride, only traces (< <1
ng/m3) of fluoride are found (Hodge and Smith, 1972). The amount of airborne
fluoride is higher in urban areas, due both to industrial pollution and to the
burning of coal and other fluoride-containing fuels; the increased burning of
fuels in the winter months can cause additional increases, in the fluoride
content of urban air (World Health Organization, 1984). Even so, the
atmospheric fluoride concentrations in urban areas rarely reach 2 ng/m3
(World Health Organization, 1984). In several studies of urban communities in
the U.S. and Europe, fluoride concentrations up to 3.8 ng/m3 were measured;
most samples contained less than 2.0 ng F/m3 (World Health Organization,
1984; Dairy etal., 1980).
Air in the immediate vicinity of industrial operations can contain larger
amounts of fluoride (World Health Organization, 1984; Drury et al., 1980).
Local airborne fluoride concentrations of 140 to 220 ng/m3 have been
measured near European aluminum plants (Drury et al., 1980). Near some
other industrial locations (primarily aluminum or phosphate processing plants),
in communities in which fluoride effects have been reported or studied,
airborne fluoride concentrations (when reported) ranged from 2.5 to 14,000 ng
F/m3 (Smith and Hodge, 1979), although in most of these cases
concentrations were less than 100 iig/m3. Smith and Hodge (1979) list more
recent ambient air fluoride concentrations near industrial operations of several
types and state that mean concentrations were nearly always less than 8.2
ng/m3 (10 ppb).
Ambient air fluoride concentrations measured 1.5 km downwind from an
aluminum processing plant in New York averaged 0.36 ng/m3 gaseous fluoride
and 0.71 ng/m3 total fluoride over a six month period (Krook and Maylin,
3-4
-------
•:.1979a). The maximum fluoride concentrations measured for a twelve-hour
period were 6.41 ng/m3 gaseous and 11.94 jig/ms total fluoride. At a location 4
km from the plant, the six-month .averages were 0.28 ng/m3 gaseous and 0.43
Iig/m3 total fluoride; the twelve-hour maximums were 2.05 ng/m3 gaseous and
5.26 iig/m3 total fluoride... Air fluoride concentrations-in the vicinity of the
Paducah (Kentucky) Gaseous Diffusion Plant reached a maximum of 1.5ng/m3
HF (1.8 ppb, from weekly measurements) in 1984 (Martin Marietta Energy
Systems, Inc., 1985); average fluoride concentrations at most sampling sites
were less than 0.082 ng/m3. in general, fluoride concentrations near industrial
sources are probably decreasing due to improved emission'control standards
and technology (World Health Organization, 1984). •.-•••
3.4. Exposure
In the middle 1970s in the United States, an estimated 22,000 workers in
57 occupations were potentially exposed to hydrogen fluoride (National Insti-
tute for Occupational Safety and Health, 1976), and 350,000 workers in 92
occupations were potentially exposed to various inorganic fluorides (National
Institute for Occupational Safety and Health, 1975). Although recent figures are
not available, the number of workers exposed to fluorides or hydrogen fluoride
is probably somewhat smaller now because of the general decrease in the
major industries which produce or use HF or other fluoride compounds.
The Occupational Safety and Health Administration (OSHA) gives a
federal occupational exposure standard for hydrogen fluoride of 2.5 mg/m3
(stated as 3 ppm) for an 8-hour time-weighted-average (TWA); the 8-hour
TWA is 2.5 mg F/m3 air for fluoride in general, including fluoride in dust, and
0.2 mg/m3 (0.1 ppm) for elemental fluorine (Code of Federal Regulations,
1985). The American Conference of Governmental Industrial Hygienists (1986)
recommends threshold limit values (TLVs) of 2.5 mg/m3 (3 ppm; this is a
ceiling1 value, not to be exceeded at any time) for hydrogen fluoride, 2.5
mg/m3 (TWA) for fluorides as F, and 2 mg/m3 (1 ppm) for fluorine. A short
term exposure limit (STEL, a 15-minute TWA) of 4 mg/m3 (2 ppm) is also
•given'for fluorine. The National Institute for Occupational Safety and Health
(1976; 1975) lists similar exposure limits for both hydrogen fluoride and
fluorides, with the addition of a ceiling on short term exposure to HF of 5.0 mg
F/m3 (6 ppm) for 15 minutes. Current occupational exposure limits in other
countries are comparable to or lower than the limits in the United' States
(International Labour Office, 1984). Occupational exposure to fluoride has been
much higher in the past than now, and much of the available information
concerning the effects of fluoride on humans has come from studies of
occupational fluoride exposure. Under current exposure limits, a maximum of
10 to 25 mg of fluoride could be inhaled in a working day (World Health
Organization, 1984). Occupational exposure to fluoride or hydrogen fluoride is
treated at length by the National Institute for Occupational Safety and Health
(1976; 1975) and by Hodge and Smith (1977; see also Smith and Hodqe
1979).
Exposure of the general public to hydrogen fluoride or other airborne
fluorides is greatest in the vicinity of point sources such as active volcanoes,
HF manufacturing plants, plants which use HF or fluorspar (including
aluminum, steel, and petroleum alkylation plants), and coal-burning facilities.
An estimated 1,075,000 people live within 8 km of 11 HF-manufacturing plants
in the United States (Boscak, 1978); the figure naturally is higher when the
other fluoride or HF sources are considered. Average total fluoride
concentrations in the vicinity of industrial operations in the U. S. and Canada
3-5
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are normally less than 8.2 ng/m3 (10 ppb) (Smith and Hodge, 1979; see also
Krook and Maylin, 1979a). Several states have ambient ain standards for
fluorides (Chester et al., 1979); these range from 0.8 ng/rn3 (Montana) to 5
ug/m3 (Pennsylvania) over a 24-hour period for fluoride as HF. The American
Industrial Hygiene Association in 1969 recommended a Community Air Quality
Guide for HF of 2.8 iig/m3 (3.5 ppb) for 24 hours (Chester et al., 1979). These
standards were established to protect vegetation and livestock; cattle health
may not in fact be adequately protected by these standards (Krook and
Maylin, 1979a), but these fluoride levels are well below those thought to cause
adverse health effects in humans (Chester et al., 1979).
People living in rural locations away from sites of industrial operations are
exposed to only trace amounts of airborne fluoride; people living in cities or in
industrial areas are exposed to proportionately more airborne fluoride. It has
been estimated that an individual living in London might inhale 0.001 to 0.004
mg of fluoride per day, possibly 5 to 10 times higher on an extremely foggy
day with high pollution (Martin and Jones, 1971, as cited in Smith and Hodge,
1979); in heavily industrialized areas, a person might inhale at most 0.01 to
0.04 mg of fluoride per day (0.0025 and 0.06 mg/day in two other studies; see
Smith and Hodge, 1979; World Health Organization, 1984). Near one
aluminum plant an estimated 0.4 to 0.7 mg fluoride per day was inhaled per
person (Smith and Hodge, 1979), but this was probably an extreme situation. If
one assumes a high value of 2 pg F/m3 air (see section 3.3 above) in urban
areas, and an inhalation volume for an adult of 20 m3 air per day, the amount
of fluoride inhaled would be 0.04 mg/day (World Health Organization, 1984). If
the airborne fluoride concentration near an industrial site were 8 ug/m3 (about
10 ppb), an adult could expect to inhale as much as 0.16 mg fluoride per day.
Acute exposure to gaseous HF rarely occurs in a nonoccupational setting, but
HF is one of several potentially toxic gases which may be encountered in fires
(Hilado and Gumming, 1978; Hilado and Furst, 1976).
The general population probably receives more fluoride via food and
drinking water than from the air. Most food items contain traces of fluoride,
and some items, particularly tea and seafood, can contain substantially more.
Fluoride intake from food ranges from 0.25 to 1.5 mg per day (Smith and
Hodge, 1979; see also Anonymous, 1986); leafy vegetables grown near
industrial fluoride sources may increase dietary fluoride by 1 to 1.7 percent.
Water sources in the United States may contain from 0.1 to 4 or more mg/L
fluoride (Safe Drinking Water Committee, 1980; Smith and Hodge, 1979). In
1980, 120 million Americans lived in areas with artificially fluoridated water
supplies (Anonymous, 1986); this water typically contains 1 mg/L fluoride in
temperate regions. Estimates for total fluoride intake from food, water, and
other beverages for people in fluoridated areas range from 1 to 5.4 mg per
day (World Health Organization, 1984; Safe Drinking Water Committee, 1980;
Smith and Hodge, 1979); 2 to 3 mg per day is probably typical, although
individual and population variations in fluoride intake probably exist.
Some individuals will also be exposed to as much as 0.8 mg of fluoride
per day from heavy cigarette smoking (Drury et al., 1980). Other potential
sources of fluoride to humans include fluoridated dentifrices and mouthwashes
(average about 0.25 mg/day); accidental intake, especially by children, of
dentifrices (see Heifetz and Horowitz, 1986) or of sodium fluoride pesticides;
exposure to fluoride-containing anaesthetic gases; and medically prescribed
use of fluoride in the treatment of osteoporosis (World Health Organization,
1984). For most people (those who do not have occupational exposure to
fluorides or hydrogen fluoride), the major source of fluoride is their food and
water. The average daily fluoride intake for people who are not in the
3-6
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immediate vicinity of industrial operations is on the order of 2 to 3 mg per day
from food and water and less than 0.1 mg fluoride per day from inhaled
fluoride.
3-7
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4. Pharmacokinetics
4.1. Absorption
Inhaled fluorides consist primarily of HF and participate fluorides, both of
which can be deposited in the respiratory tract (World Health Organization,
1984). Hydrogen fluoride, most of which is probably deposited in the upper
respiratory tract, is rapidly absorbed into the system, either directly from the
respiratory tract or following translocation to the gastrointestinal tract via nasal
mucus (Morris and Smith, 1982). Close to 100 percent of inhaled HF is
absorbed (Machle and Largent, 1943). Depending on the size and nature of
the particles, fluoride-containing particles may be exhaled without being
deposited on the surface of the respiratory tract, or they may be deposited in
the nasopharynx, the tracheobronchial tree, or the alveoli (World Health
Organization, 1984). Absorption of these fluorides and of ingested fluorides is
dependent on several factors, including the chemical nature of the fluorides
and what other substances have also been ingested. Fluoride from inhaled
dust is absorbed as rapidly as fluoride from inhaled HF, but for a given
airborne fluoride concentration, less total fluoride is absorbed from fluoride-
containing dust than from gaseous fluoride compounds (Collings et al., 1951).
Soluble fluoride salts (e.g., fluorides in fluoridated water) are absorbed very
rapidly by the gastrointestinal tract. The presence of fluoride-binding cations
such as calcium or aluminum will result in greatly reduced fluoride absorption
in the gastrointestinal tract (World Health Organization, 1984; Drury et al.,
1980; Spencer et al., 1980), thereby increasing fluoride excretion in the feces.
In experiments with human subjects, Machle and Largent (1943) observed
approximate gastrointestinal absorptions of 97 percent for NaF and 95 percent
for CaF2 administered in solution. Only 60 percent of solid CaF2 was absorbed
in the gastrointestinal tract, the rest being excreted in the feces. The low pH of
the stomach permits some otherwise insoluble fluoride compounds to be
dissolved, causing generation of HF gas in the stomach (World Health
Organization, 1984). Hydrogen fluoride is rapidly absorbed from the
gastrointestinal tract, as from the respiratory tract; absorption of HF through
the skin has also been observed in workers suffering hydrofluoric acid burns in
accidents (World Health Organization, 1984; Tepperman, 1980; Burke et al.,
1973).
Absorption of any fluoride appears to be a passive process (Drury et al.,
1980). Fluoride from any source is thought to be transported across biological
membranes primarily as molecular HF (Whitford and Pashley, 1984;
Gutknecht and Walter, 1981; Whitford et al., 1976). At physiological pH (in
blood, intracellular fluid, or mucus), fluoride from any source exists primarily
as fluoride ion (F~), although a small amount of molecular HF exists in
equilibrium with the ion. The fate or effects of absorbed inorganic fluoride are
essentially independent of the fluoride source.
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4.2. Retention and Distribution
Approximately 35 to 50 percent of absorbed fluoride from any source is
retained in the human body (World Health Organization, 1984;. Hodge and
Smith, 1965); the (human) subjects" of Machle and Largent (1943)
demonstrated about 60 percent retention of absorbed fluoride (total, daily
intake, >6.0 mg/day). At low fluoride intakes (non-occupational, <4.0 to 5.0
mg/day), there may be very little cumulative storage of fluoride (McClure et al.,
1945). About 99 percent of retained fluoride is found in the skeleton, the rest in
the blood and in other tissues (World Health Organization, 1984). Fluoride is
transported through the body via the bloodstream. About three-fourths of the
blood fluoride is in the plasma; the remainder is in or on the red blood cells
(World Health Organization, 1984). At least one-half of the fluoride in human
serum may be nonionic fluoride; this includes both organic fluoride
(perfluorinated fatty acid derivatives) and nonionizable fluoride formed from F"
or HF, and the amount of nonionic fluoride is related to the total fluoride intake
(World Health Organization, 1984; Morris and Smith, 1983; Ophaug and
Singer, 1977).
For the general population at a steady-state exposure to fluoride, the
plasma concentration of inorganic (ionic) fluoride is directly related to the
inorganic fluoride content of the drinking water (World Health Organization,
1984; Drury et al., 1980). The normal range of plasma fluoride concentrations
is about 10 to 20iig/L in areas with low water fluoride levels (less than or
equal to 1 mg/L; World Health Organization, 1984; Drury et al., 1980; Smith
and Hodge, 1979). An average blood fluoride concentration of about 82 ng/L
was found in a community with 5.6 mg/L fluoride in the drinking water (Drury
et al., 1980; Smith and Hodge, 1979). Blood fluoride levels in fatal cases of
acute fluoride poisoning have ranged from 3.5 to 15.5 mg/L (Gosselin et al.,
1984). Plasma concentrations of fluoride increase with age, possibly because
clearance from the blood via uptake into bone is slower in adults than in
children. Clearance of fluoride from the blood occurs rapidly by incorporation
into bone and by renal absorption and excretion. Young bone (i.e., in chil-
dren), presumably because it is less saturated with fluoride, appears to take
up fluoride more rapidly than does bone in older individuals; children there-
fore excrete less fluoride in the urine than do adults.
The fluoride ion taken up by bone replaces hydroxyl ions in bone apatite
(World Health Organization, 1984). The precise mechanism of fluoride
incorporation into bone is still under investigation (see World Health
Organization, 1984; Rioufol et al., 1983; Drury et al., 1980); the overall result is
that absorbed fluoride is incorporated into the hard tissues primarily by an
exchange process (the displacement of hydroxyl groups) and by incorporation
into the apatite lattice during bone mineralization. The amount of fluoride in
bone is dependent on an individual's age, sex, fluoride intake, and the specific
type and part of bone being examined. Fluoride accumulates in the bone with
increasing age, although the rate of incorporation decreases; higher bone
fluoride concentrations are also found in individuals or groups with greater
fluoride exposure. Long-term (60 years) intake of 1 mg/L fluoride in water can
cause a fluoride level of 4000 mg/kg of dry fat-free bone (Drury et al., 1980).
An intake of 8 mg/L for 35 years would cause a bone fluoride level of 6000
mg/kg, the level necessary for detection of osteosclerosis, which is defined as
an increased opacity of the bone to X-rays,, Surface regions of bones
incorporate fluoride more rapidly than interior, regions, and cancellous
(spongy) bone more than cortical (compact) bone. Fluoride can be released
from bone (when intake decreases), and has a removal half-life of 8 to 10
4-2
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years (Grandjean, 1982; Drury et al., 1980; Forbes et al., 1978). If fluoride
intake is decreased following a period of fluoride storage, the urinary fluoride
level may exceed the current fluoride intake, resulting in a net loss of fluoride
.from the body (Grandjean, 1982; llargent, 1952). Fluoride is incorporated into
teeth in a similar manner to its incorporation into bone (World Health
Organization; 1984)> Unlike bone, which can continue to take up fluoride
throughout an individual's lifetime, teeth incorporate fluoride only during their
period of calcification (up to about age 12 in humans; Drury et al., 1980).
Only very small amounts of fluoride are found in the soft tissues of the
body (with levels generally highest in the kidneys; Hejfetz and Horowitz, 1986,
Hodge and Smith, 1965), and these levels do not increase with age (World
Health Organization, 1984; Drury et al., 1980; see also Knaus et al., 1976).
Tissue fluoride concentrations are approximately in equilibrium with plasma
fluoride concentrations. Sites of ectopic calcification of soft tissues, such as
tendons, cartilage, aorta, or placenta, may accumulate fluoride.
4.3. Excretion
Approximately half of the absorbed fluoride is excreted in the urine (World
Health Organization, 1984; Drury et al., 1980); this is the major route of fluoride
clearance from the blood and from the body. Renal fluoride excretion involves
glomerular filtration followed by pH-dependent tubular reabsorption.
Reabsofption occurs by nonionic diffusion of HF (see Whitford et al., 1976),
and therefore is greater in acidic urine than in alkaline urine (i.e., fluoride
'removal from the body is greater in alkalosis than in acidosis; see Smith,
1986b; Whitford et al., 1979; Reynolds et al., 1978). Urinary fluoride is an
important indicator of fluoride exposure, and it is routinely used to measure
occupational fluoride absorption (Jackson and Hammersley, 1981; National
Institute for Occupational Safety and Health, 1976; 1975). For the general
population, a good correlation exists between urinary fluoride concentrations
and fluoride concentrations in drinking water (World Health Organization,
1984). For one group of "people drinking low-fluoride water (<0.2 mg/L) and
receiving' no occupational exposure to fluoride, the average urinary fluoride
level was found to be 0.61 mg/L (upper limit, 2.00 mg/L; after correction for a
specific gravity for the urine of 1.024, the average fluoride level was 0.74 mg/L
and the upper limit was 3.9 mg/L; Massmann, 1981). Urinary fluoride
concentrations of 9 mg/L or greater (corresponding to occupational exposure
to more than 2.5 mg/rris fluoride in the air or to exposure to 8 mg/L fluoride in
the drinking water) are associated with a higher incidence of osteosclerosis
(Smith and Hodge, 1979). Preshift urinary fluoride levels below 5.3 mg/L have
not been associated with' osteosclerosis in workers, and a preshift level of 4
mg/L is thought to provide an adequate margin of protection (National Institute
for Occupational Safety and Health, 1976; Derryberry et al., 1963; Largent,
1961). Non-occupationally exposed people whose drinking water contains less
than 4 mg/L fluoride are 'also considered not to be at risk of developing
osteosclerosis (National Institute for Occupational Safety and Health, 1976).
Urinary excretion of fluoride is decreased in cases of renal failure or
disfunction, and retention (i.e., bone deposition) of fluoride increases
accordingly (Kono et al., 1984a; 1984b; Gerster et al., 1983). People .with
renal disfunction are therefore at a higher risk of adverse health effects due to
fluoride. ': •
Some fluoride is also excreted in the feces, sweat, saliva, and milk (World
Health Organization, 1984). Fluoride in the feces is primarily ingested fluoride
that was not absorbed, ah'd fluoride excreted into the gastrointestinal tract
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does not appear to be a major source of fecal fluoride (Machle and Largent,
1943). That some fluoride can be excreted into the gastrointestinal tract is
suggested by the findings of Largent (1961), in which the fecal fluoride content
of human volunteers increased (2.5- to 6.7-fold, highest value was 0.700
mg/day) during a period (2 to 4 weeks) of HF inhalation (0.74 to 6.6 mg/m3),
average individual exposures between 1.2 and 3.9 mg/m3, 6 hours per day).
No coincident increase in oral fluoride intake (food or water) was noted which
might have accounted for the observations. Sweat can be an important route
of fluoride removal in people who are very active or live in hot climates and
whose water intake is therefore very high, but normally only very small
amounts of fluoride are found in sweat, saliva, or milk. Fluoride concentrations
in sweat of 0.3 to 1.8 mg/L were reported in humans ingesting up to 4.0 to 5.0
mg fluoride per day; 2 weeks after termination of the experiment (returning to
normal dietary fluoride intake), the measured fluoride in the subjects' sweat
was 0.2 to 0.3 mg/L (McClure et al., 1945). Salivary fluoride concentrations are
proportional to plasma fluoride concentrations, while the fluoride concentration
in human milk is independent of the plasma fluoride level and therefore of
maternal fluoride intake (Ekstrand et al., 1981). Observed fluoride levels in
human milk are between 2 and 8ug/L, less than those in most milk substitutes.
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5. Mutagenicity and Carcinogenicity
5.1. Mutagenicity
'••• Several authors have suggested the potential mutagenicity of either
hydrogen fluoride or sodium fluoride to plants, Drosophila, or mammals (see
for instance Caspary et al., 1987; Cole et al., 1986; Tsutsui et al., 1984a;
1984b; 1984c; Mohamed, 1977; Voroshilin et al., 1975; 1973; Gerdes, "1971;
Gerdes et al., 1971; Mohamed and Kemner, 1969). On the other hand,
Leonard et al. (1977) found no increase in chromosome Aberrations In "the
leukocytes of cattle with chronic fluoride poisoning, nor did Voroshilin et al.
(1973) in human leukocytes treated in vitro with sodium fluoride. Temple and
Weinstein (1978) were unable to demonstrate mutagenicity of HF in tomato
plants. Martin et al: (1979) found no evidence for increased chromosome
aberrations in mice following exposure to sodium fluoride, nor'did they find
sodium fluoride to be mutagenic in a bacterial (Salmonella) mutagenesis
assay. A review by the International Agency for Research on Cancer (1982)
did not find sodium fluoride mutagenic in Salmonella or Drosophila, and both
the United States Environmental Protection Agency (Federal Register, 1985b)
and the National Research Council (Safe Drinking Water Committee, 1977)
conclude that the mutagenicity of fluoride to man has not been demonstrated.
Tsutsui et al. (1984a; 1984b; 1984c) found evidence for DNA damage in
cultured human or Syrian hamster cells, including both chromosome
aberrations and unscheduled DNA synthesis, following treatment with 50 to
400 mg/L sodium fluoride in the extracellular medium. Cole et al. (1986)
concluded that at high (and highly toxic) concentrations (up to 500 mg/L),
sodium fluoride caused a small increase in mutation frequency in cultured
mouse lymphoma cells, mainly as a result of chromosome breakage; at 10
mg/L fluoride in the medium there was no significant effect. Caspary et al.
(1987) demonstrated mutagenic effects in mouse lymphoma cells of both
sodium fluoride and potassium fluoride, at concentrations in the range of 300
to 700 mg/L. Tsutsui et al. (1984c) point out that genotoxicity of sodium
fluoride has been demonstrated in many in vitro studies but in very few in vivo
studies. The fluoride concentrations used to induce genotoxic effects in these
experiments (50 to 700 mg/L) are 2,500 to 70,000 times greater than the
normal blood fluoride range (10 to 20 ng/L in humans; World Health
Organization, 1984; Drury et al., 1980; Smith and Hodge, 1979). A blood
fluoride concentration of 80 pg/L (corresponding to a drinking water level of 5.6
mg/L; Drury et al., 1980; Smith and Hodge, 1979) would still be 600 to 6,000
times lower than the concentrations shown to cause chromosome damage.
Martin et al. (1979) studied chromosome aberrations in bone marrow and
testis cells of mice exposed to sodium fluoride. They found no evidence for an
increased frequency of chromosome aberrations in mice with a fluoride intake
of 50 mg/L in the drinking water for several generations or in mice with an
intake of 100 mg/L for 6 weeks. Oral doses of sodium fluoride (up to 84 mg/kg)
did not induce DNA-strand breaks in the testicular cells of rats, even when
plasma fluoride reached (temporary) concentrations of 11 to 12 mg/L at 2
hours after dosing (Skare et al., 1986a); testicular fluoride levels did not
exceed 1 mg/L; suggesting that sodium fluoride does not pose a heritable
genetic hazard.
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Sodium fluoride has been shown to cause a dose-dependent decrease in
the amount of DNA replication in cultured WI-38 (human) cells (Skare et al.,
1986b). Fluoride ion is known to inhibit many enzymes, and any effects of
fluoride on DNA or chromosomes are more likely the result of fluoride inhibi-
tion of DNA repair or replication enzymes than of interaction of fluoride with
DNA itself (Cole et al., 1986; Skare et al., 1986b).
5.2. Carcinogenicity
No specific epidemiological;evidence is available for the evaluation of the
potential carcinogenicity to humans of hydrogen fluoride or other inhaled
fluorides. Increased rates of cancer have been reported for workers in several
occupations involving possible fluoride exposure, including aluminum produc-
tion, fluorspar mining, and stainless steel pickling (Grandjean et al., 1985;
World Health Organization, 1984; Ahlborg et al., 1981; de Villiers and Windish,
1964). However, all these situations involved mixed exposures to several
chemicals (e.g., radon in fluorspar mining, polycyclic aromatic hydrocarbons in
aluminum production, and metal compounds and irritating acids in the
stainless steel pickling house), and fluoride could not be specifically implicated
as the cause of the cancers (Grandjean et al., 1985; World Health
Organization, 1984; Ahlborg et al., 1981; Drury et al., 1980; de Villiers and
Windish, 1964). Correlation has also been demonstrated between cancer rates
and industrial pollution from steel mills, which emit fluoride among other
things; again, no specific pollutant could be identified as the major cause of
the increased cancer rates (Drury et al., 1980).
The possible carcinogenic potential of fluoride in drinking water has been
investigated by comparing rates of cancer in areas with artificially or naturally
high fluoride levels in drinking water with the corresponding rates in low
fluoride areas. The International Agency for Research on Cancer (1982)
concluded that when "proper account was taken of the differences among
population units, in demographic composition, and in some cases also in their
degree of industrialization and other social factors, none of the studies
provided any evidence that an increased level of fluoride in water was
associated with an increase in cancer mortality." The National Research
Council (Safe Drinking Water Committee, 1977) and the United States
Environmental Protection Agency (Federal Register, 1985b) also agree that the
available information does not suggest that fluoride ixn the drinking water has
increased the rate of cancer mortality. The United States Environmental
Protection Agency (Federal Register, 1985b) states that "there is not enough
information to conclude that fluoride presents a cancer risk to humans" but
has not officially classified fluoride or hydrogen fluoride with respect to
carcinogenicity.
No animal bioassays have been reported on the potential carcinogenicity
of inhaled fluorides. The International Agency for Research on Cancer (1982)
reviewed tests of sodium fluoride administered orally to mice and found the
data insufficient to permit evaluation. Hydrogen fluoride has been suggested
as a contributing factor in the production- of lung cancer from cigarette
smoking (Sutton, 1986), but no specific evidence is available in support of this
idea. The available evidence is thought to be inadequate to support or refute a
carcinogenic potential for inhalation exposure to fluorides.
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6. Developmental and Reproductive Toxicity
Few reports are available concerning women with industrial fluoride
exposure (Smith and Hodge, 1979; Hodge and Smith, 1977). The one available
•epidemiological study of female workers in a superphosphate plant found a
- higher incidence of gynecological problems (e.g., menstrual irregularities,
vaginal .and uterine inflammation, toxicosis during pregnancy, untimely dis-
charge of amniotic fluid) in production workers than in the control group of
office workers and housewives (Smith and Hodge, 1979; Hodge and Smith,
1977). The production workers were exposed to dust concentrations of 5 to 57
mg/m3 and fluoride concentrations of 0.3 to 2.8 mg/m3. The menstrual
irregularities were correlated with dust concentrations, but specific information
is not available on possible correlation of gynecological problems with fluoride
concentrations in the workplace air or in the urine of the workers. No
difference between groups was found in the numbers of pregnancies,
miscarriages, or births. No reports of increased incidence of either
spontaneous abortions or births of abnormal fetuses have come from
communities in the United States with natural fluoride levels of 4 mg/L or more
in the drinking water (Smith and Hodge, 1-979; Hodge and Smith, 1977). The
United States Environmental Protection Agency (Federal Register, 1985b)
concludes that there is inadequate evidence to support an association
between fluoride in U.S. drinking water and either reproductive or teratogenic
effects.
Fluoride is known to cross the placenta and to be deposited in the calci-
fied tissues of the fetus (see Smith et al., 1982; Crissman et al., 1980;
Maduska et al., 1980; Rioufol et al., 1980; Krook and Maylin, 1979a; 1979b;
Smith and Hodge, 1979). Although fetal exposure is proportional to maternal
exposure, the fluoride level in umbilical cord blood increases more slowly than
the level in maternal blood; the fetal blood level of fluoride is only about 75
percent of the level in maternal blood. Largent cities a case report of acute
fluoride poisoning (ingestion of 50 to 80 g NaF) in a sixteen-year-old girl who
was in her 6th week (approximately) of pregnancy (Peters, 1948, cited in
Largent, 1961). She was-in serious condition at first, but received adequate
treatment and recovered within a week; she eventually gave birth to a normal,
full-term son. Blood fluoride concentrations were not measured at the time of
the poisoning or at the birth of the child.
Excess fluoride in the air, water, or food has caused impaired reproduc-
tion in Drosophila (Gerdes et al., 1971), mice (Messer et al., 1973), rats (Smith
and Hodge, 1979; Hodge and Smith, 1977), and cattle (Crissman et al., 1980;
Krook and Maylin, 1979a; 1979b; Safe Drinking Water Committee, 1977).
Fluoride doses of 2.5 mg/kg body weight caused cessation of the estrus cycle
in rats, and intake of 10 and 150-300 mg/kg caused endocrine malfunction in
guinea pigs and rats, respectively (Smith and Hodge, 1979; Hodge and Smith,
1977). Too low a fluoride intake also caused decreased reproductive
performance in mice (Messer et al., 1973), but although the essentiality of
fluoride to humans has not been satisfactorily demonstrated, fluoride
deficiency is not likely to occur in man because of the ubiquity of fluoride in
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normal humans diets (Smith, 1986b). Fluoride doses of 1 mg/kg or more have
caused bone and tooth malformations in dog, rat, and mouse fetuses (Drury et
al., 1980; Hodge and Smith, 1977), and embryo and fetal toxicity from high
doses of fluoride (3 to 50 mg/kg/day, dependent on species) have been
reported in experimental mammals (Smith and Hodge, 1979). If a 50 kg female
worker were exposed to 2.5 mg F/m3 (the maximum permitted under current
occupational standards), she would inhale an estimated 25 mg fluoride per
day. If all the inhaled fluoride were actually absorbed (which is not the case),
she would receive a maximum of 0.5 mg F/kg/day, which is still less than the
fluoride doses necessary to cause toxic effects on reproduction or
development in experimental animals. Hodge and Smith (1977) estimate that
the toxic doses in animals are 10 to 200 times greater than the total
occupational fluoride intake of the 50 kg female worker, and they conclude that
the occupational standard is adequate to protect the pregnant woman and her
fetus. Machle and Kitzmiller (1935) reported that a rabbit exposed to 15.2 mg
HF/m3 (about 6 times the occupational exposure standard) for 309 hours (6-7
hours per day over about 10 weeks) became pregnant during the exposure
period and gave birth to 3 apparently normal offspring 13 days after the
exposure ended. The human data that is available at this time does not
suggest that HF poses a developmental risk.
Some reports have suggested an increased risk of Down's syndrome
associated with fluoridated water (Rapaport, 1963; 1959; 1956; cited in World
Health Organization, 1984), but the current consensus is that fluoride has no
influence on the incidence of Down's syndrome (World Health Organization,
1984; Shepard, 1983; Smith et al., 1982; Drury et al., 1980; Safe Drinking
Water Committee, 1977; Hodge and Smith, 1965). One study does suggest
that fluoride has some effect, probably beneficial, on fetal growth in humans
(see World Health Organization, 1984).
The major developmental risk to humans from fluoride from any source is
dental mottling or fluorosis (staining or pitting of the teeth caused by
hypomineralization of the enamel; Heifetz and Horowitz, 1986). Fluorosis
occurs in individuals receiving excess fluoride during the period of tooth
calcification: prior to birth for the deciduous teeth and up to age 12 for the last
of the permanent teeth. The discoloration and pitting are the result of a
disturbance affecting the formation of the enamel; damage occurs before the
eruption of the teeth (World Health Organization, 1984). Fluorosis can occur in
the deciduous teeth of a child when the mother's fluoride intake during
pregnancy is high (Grandjean, 1982; Smith and Hodge, 1979); most fluorosis
occurs in the permanent teeth and is caused by the child's own high fluoride
intake. Fluorosis of the deciduous teeth is naturally of lesser concern than
fluorosis of the permanent teeth. The severity of dental fluorosis increases with
increased fluoride dose; mild fluorosis occurs at fluoride levels of 1.5 to 2
mg/L in the drinking water (World Health Organization, 1984).
The United States Environmental Protection Agency (1986) gives a No
Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect
Level (LOAEL) of 1 and 2 mg/L (1 and 2 ppm) fluoride in the drinking water,
respectively, using dental fluorosis as the endpoint. The Agency has
established a Reference Dose (RfD) for oral exposure to fluoride of 0.06
mg/kg/day (U.S. Environmental Protection Agency, 1986). This level
corresponds to the fluoride intake expected for a 20-kg child if the water
fluoride level is 1 mg/L (the NOAEL). Fluoride intake at this level does not
cause dental fluorosis in the sensitive population (children), nor does it cause
skeletal fluorosis in adults (United States Environmental Protection Agency,
1986). The Agency does, however, consider dental fluorosis to be a cosmetic
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effect rather than a health effect (Federal Register, 1985b,), and permits
(natural) fluoride levels in the drinking water up to 4 mg/L (4 ppm), a level at
which fluorosis, but not in its severest form, does occur.
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7. Other Toxic Effects
7.1. Acute Toxicity
Acute exposure to hydrogen fluoride, fluorine, or other gaseous fluorides
is rare outside of an occupational setting, although some solutions containing
hydrofluoric acid (usually less than 20 percent) are available to the public
(Jordan, 1982). The toxicity of some gaseous fluorine compounds decreases
in the following order: F2O, F2, HF, BF3, and H2SiF6 (World Health
Organization, 1984); these compounds can severely damage the skin and
respiratory tract of individuals exposed to them. Hydrogen fluoride can be
detected by smell at concentrations of less than 1 mg/m3 (Amoore and
Hautala, 1983), and no health effects are observed at 2.6 mg/m3, but irritation
of eyes and respiratory passages is noticed in less than 10 minutes at 26
mg/m3 or at 13.33 mg/m3 if exposure is longer than 10 minutes (Just and
Emler, 1984; Just, 1984). The Immediately Dangerous to Life or Health (IDLH)
level is 16.4 mg/m3 (20 ppm; Sittig, 1985). [The IDLH level is "the maximum
level from which one could escape within 30 minutes without any escape-
impairing symptoms or any irreversible health effects" (Just and Emler,
1984).] Machle et al. (1934) reported that the highest concentration of HF
tolerated by human volunteers for more than 1 minute was 100 mg/m3; at this
level conjunctiva! and respiratory irritation was marked, the taste of the gas
pronounced, and definite smarting of the skin noted. Irritation and taste were
noted also at 50 mg/m3. There was discomfort at 26 mg/m3, but the
atmosphere could be tolerated for several minutes (Machle et al., 1934)!
Williams (1942) reported irritation and a runny nose (with occasional bloody
discharge after 20 minutes) at concentrations above 10 mg/m3. Fluorine gas
causes almost immediate nasal and eye irritation at a concentration of 25 to 40
mg/m3 and is intolerable at 40 mg/m3 (Just and Emler, 1984); the IDLH level is
50 mg/m3 (25 ppm; Sittig, 1985). Symptoms of HF and F2 inhalation are
similar and include irritation, coughing, and choking followed eventually by
symptoms of pulmonary edema (World Health Organization, 1984). Death from
hemorrhagic pulmonary edema and destruction of lung tissue may occur
(Braun et al., 1984; Gosselin et al., 1984; Kleinfeld, 1965; Mayer and Guelich,
1963). Most available case reports of HF inhalation describe death from
pulmonary edema or cardiac and respiratory failure, and no information on
long-term pulmonary damage in patients surviving acute HF inhalation is
available. In a case of inhalation exposure to mixed hydrofluoric and sulfuric
acid, described by Braun et al. (1984), the' surviving patient exhibited no
obvious pulmonary impairment, but he did continue to have upper respiratory
tract problems (hoarseness, coughing, pain, nc-se bleeds) one year after the
exposure.
Machle et al. (1934) reported that exposure to 1,000 to 1,500 mg HF/m3
for 5 minutes produced death in a significant proportion of rabbits and guinea
pigs. Damage to liver, kidney, and lungs was observed in animals exposed to
as little as 24.5 mg HF/m3 (41 hours total exposure, 6 hours/day, autopsied 18
hours post-exposure; no deaths occurred in animals with similar exposure
7-1
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observed for 1 year following exposure; Machle and Kitzmiller, 1935; Machle
et al., 1934). Rosenholtz et al. (1963) reported LC50 (lethal concentration for 50
percent of the exposed population) values for rats of 4,060, 2,200, 1,670, and
1,070 mg HF/m3 for 5, 15, 30, and 60 minutes, respectively, and for guinea
pigs of 3,540 mg/nr>3 for 15 minutes. Inhalation of 25 mg/m3 HF for 166 hours
total produced 100 percent mortality in rats and mice, but no mortality in
guinea pigs, rats, or dogs (Hodge and Smith, 1965). No deaths occurred in
any species at 7.2 mg HF/m3. Exposure to fluorine (F2) at concentrations as
low as 315 mg/m3 for 3 hours killed all exposed animals (several species)
within 14 days. At lower concentrations, guinea pigs appeared to be less
susceptible than rats, mice, and rabbits. For 170 hours exposure to 25 mg/m3
F2, both rats and guinea pigs exhibited 50 percent mortality (Hodge and
Smith, 1965; Stokinger, 1949).
LC5o values for mice and rats (without any attempt to estimate human
values) have been reported by Vernot et al. (1977) and MacEwen and Vernot
(1971). For a 5 minute exposure to HF gas and a 7 day observation period,
LC50 values of 5,120 mg/m3 (6,247 ppm; 95% confidence limits of 4,789 and
8,149 ppm) and 14,900 mg/m3 (18,200 ppm; 95% confidence limits of 15,965
and 20,748 ppm) were obtained for mice and rats, respectively (MacEwen and
Vernot, 1971). For a 60 minute exposure, the LC50 values for mice and rats,
respectively, were 374 mg/m3 (456 ppm; 95% confidence limits of 426 and
489 ppm) and 792 mg/m3 (966 ppm; 95% confidence limits of 785 and 1,190
ppm) (Vernot et al., 1977). MacEwen and Vernot report that, following a 5
minute exposure to HF, most of the exposed animals experienced pulmonary
edema of varying severity, and pulmonary hemorrhage was a common finding
in animals which died during or shortly after exposure to HF concentrations
above the LC50 value. The available LC values for HF inhalation are
summarized in Table 7-1.
Contact of HF or hydrofluoric acid with the skin results in deep, severe
burns (Gosselin et al., 1984; World Health Organization, 1984; Mackison et al., '.
1981; Stokinger, 1981; Drury et al., 1980; Jordan, 1982; Loriot et al., 1981;
Greendyke and Hodge, 1964). Fluorine causes thermal burns on the skin (from
reaction with the skin) rather than the deep necrosis characteristic of HF burns
(World Health Organization, 1984). Solutions of less than 60 percent
hydrofluoric acid probably do not pose an inhalation hazard, but skin burns
can occur even from low concentrations of hydrofluoric acid (Jordan, 1982).
Burns from solutions of less than 20 percent HF may not be noticed for up to
24 hours following skin contact, while solutions greater than 50 percent HF
cause immediate pain and tissue damage. Death from systemic fluoride
poisoning may occur from HF absorbed via the lungs or the skin (Gosselin et
al., 1984; Kono et al., 1982; Tepperman, 1980; Burke et al., 1973). Derelanko
et al. (1985) found that dilute (2 percent) concentrations of HF were corrosive
to rabbit skin following exposures as short as 5 minutes and that significant
absorption of fluoride occurred through the skin. Serum fluoride levels were
elevated by 3-fold and 5- to 6-fold following exposure to 2 percent HF for 1
and 4 hours, respectively, and were still significantly elevated 48 hours post-
exposure. In rats, systemic fluoride poisoning and death occurred following
exposure of 1.7 percent of the body surface to 50 percent HF for 5 minutes
(Kono et al., 1982; inhalation of HF by the test, animals was prevented). The
mortality rate was about 80 percent within 24 hours of treatment. In animals
dying within 4 hours of treatment, serum fluoride levels varied from about 80
to 200 times the control level, while serum ionic calcium levels were one-third
to one-fiftieth of the control level. Tepperman (1980) and Burke et al. (1973)
7-2
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Table 7-1. -Summary of Lethal Concentration (LC) Estimates for HF Inhalation
.' Concentration ' Type '
LC' Concentration Tim x Time - of ''•' •
Level mg/m3 min mg/m3 x min Data ' , Source
LCso
LC50 '
LCioo
LC-ioo
' .5,120.
14,900 '
374-
792
148"
1 05,'OOQ
26,000
' 10,500
5;250
.877 <
1
5a
5a
"60
60
360,
0.5
2
5
10
60
25,600
74,500
22,440
47,500
53,280
52,500
52,000
52,500
52,500
52,620
mouse
rat ' " ''
mouse .
rat
rat"
' -
estimate
for humanb
estimate'
for humanb
estimate ,
for humanb,
estimate
for humanb
estimate
for huma'nb •
. ..MacEwen .-
and
Vernot (1971)''
Vernot et a'l.
(1977)'
Morris and '
Smith (1982)
:' Just (1984);
" Just and
Elmer (1984)
aLC values determined for 5 minute exposure, 7 day observation for mortality. • •
bEstimated directly from animal (rat) data without any adjustment. • • • .
report cases of fatal'or near fatal systemic poisoning in humans following HF
burnsof only 2.5 percent of the body surface. • • '
" Ingested fluorides (sodium fluoride, for instance) are lethal at a dose of 32
to 64 mg fluoride per kg body weight, or about 2.2 to 4.5 g 'for an adult
(Heifetz and Horowitz, 1986; Dfury et al., 1980). This corresponds to a. dose of
5 to 10 g (70 to 140 mg/kg) of NaF (Heifetz and Horowitz, 1986; Gosselin et
al., 1984; World Health Organization, 1984; Drury et al., 1980). This is in
keeping with the findings of Lu et al. (1965) of acute lethal doses of fluoride,
administered by intravenous infusion at 1 mg/kg/min, of 26.6, 60.0, arid 65.8
mg/kg for squirrel monkeys, albino rats, and Rhesus monkeys, respectively.
An acute dose of 8 to 16 mg fluoride per kg body weight can be safely
tolerated by humans (Heifetz and Horowitz, 1986). The toxicity of specific
fluoride compounds varies primarily with their ease of absorption (Drury et al.,
1980). Symptoms of acute toxicity following the ingestioh'of fluoride include
nausea arid vomiting, caused by local irritation of the gastrointestinal tract
(Heifetz and Horowitz, 1986). ;High doses result in systemic poisoning, with '
symptoms including -convulsions and cardiac arrhythmias (Heifetz-and
Horowitz, 1986; Baltazar et al., 1980; Abukurah et al., 1972). One report
suggests that pulmonary damage due to inhibition of surfactant synthesis may
also result from systemic fluoride poisoning, even if the fluoride was not
inhaled'(Gaugl and Wooldridge, 1983). Death from acute fluoride poisoning,
whether from HF inhalation or burns or from ingestion of fluoride salts, is
usually from cardiac or respiratory failure and generally occurs within 24 hours
(Heifetz'and Horowitz, 1986; Stokinger, 1981). ', ,
7-3
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Serum fluoride concentrations of 3 to 15.5 mg/L have been associated
with fatal cases of fluoride poisoning, both from oral ingestion of fluorides and
from skin burns or inhalation of HF (Gosselin et al., 1984; Tepperman, 1980;
Yolken et al., 1976; Hodge and Smith, 1965; Greendyke and Hodge, 1964),
although one case has been reported in which the serum fluoride level at
autopsy was only 67 ng/L (Braun et al., 1984). Most instances of survival of
fluoride or HF poisoning are associated with serum fluoride levels below 3
mg'L (Burke et al., 1973), although one victim of oral fluoride (Na2SiF6)
poisoning survived despite a serum fluoride of 14 mg/L 6 hours after ingestion
of the poison (Yolken et al., 1976). The major route of clearance of excess
fluoride from the body following poisoning is the urinary system, and urinary
fluoride levels as high as 87 mg/L (3-1/2 hours after the accident) have been
reported in survivors (Burke et al., 1973; Yolken et al., 1976). Fluoride
concentrations are also increased in soft tissues following fatal intoxication.
Levels of 10.6 mg/kg, 4.6 to 11.6 mg/kg, 4.4 to 11.2 mg/kg, and 12.4 to 15.6
mg/kg have been reported in heart, kidney, liver, and lung tissue, respectively,
following fatal intake of sodium fluoride (Hodge and Smith, 1965).
7.2. Chronic Toxicity
Chronic exposure to low concentrations (level not specified, but in the
context of occupational exposure) of hydrofluoric acid vapors may produce
chronic irritation and congestion of the nose, throat, and bronchi (Evans, 1965;
cited in Hodge and Smith, 1965). Most other manifestations of chronic fluoride
toxicity are dependent solely bn the intake of fluoride ion, independent of the
source or route of exposure (e.g., HF vs. NaF, airborne vs. waterborne) (Hodge
and Smith, 1965). The bones and teeth are the tissues most sensitive to long-
term fluoride intake. Dental mottling or fluorosis occurs in humans when
fluoride intake is high during the years of tooth calcification to age 12, usually
before age 8; see section 6 for discussion). Mild fluorosis can occur with a
fluoride intake of about 0.1 mg/kg/day (corresponding to a level of 1.5 to 2
mg/L fluoride in the drinking water); fluorosis (in some cases severe) is
common when fluoride intake is 0.2 to 0.35 mg/kg/day (>4 mg/L fluoride in
drinking water; see United States Environmental Protection Agency, 1986;
Federal Register, 1985a; 1985b; World Health Organization, 1984; Hayes,
1982).
Long-term fluoride intake of 0.2 to 1.0 mg/kg/day or more can result in
skeletal fluorosis (Hayes, 1982); this amount corresponds to a level of 4 mg/L
or greater in the drinking water or an air concentration of 12 to 26 mg/m3
(most likely an occupational exposure; Federal Register, 1985a; Hayes, 1982).
Kaltreider et al. (1972) reported skeletal fluorosis, with no physical impair-
ment, in a majority of potroom workers in an aluminum plant following
exposure to "high concentrations" (2.4 to 6.0 mg/m3, 8-hr TWA; urinary
fluoride >8.7 mg/L) for 10 years. Others workers exposed up to 40 years to
lower fluoride concentrations (post-shift urinary fluoride <4.6 mg/L, pre-shift
fluoride < 1.6 mg/L) did not show any evidence of skeletal fluorosis.
Skeletal fluorosis is defined as an accumulation of fluoride in the skeletal
tissues associated with pathological bone formation (World Health
Organization, 1984). The earliest observable effect of fluoride deposition in the
skeleton is an increased opacity of the bone to X-rays, known as osteo-
sclerosis (Federal Register, 1985a, 1985b; World Health Organization, 1984;
Hayes, 1982). Osteosclerosis is first noticeable when the fluoride level reaches
5000 to 6000 mg/kg of dry, fat-free bone (World Health Organization, 1984), a
level which corresponds to an intake of 8 mg/LJ!uoride in the drinking water
7-4
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for 35 years (Dairy et al., 1980). Skeletal fluorosis increases in severity with
increased fluoride intake, and increased time. Prolonged high fluoride intake
can cause "crippling fluorosis," which is characterized by pain, stiffness,
irregular bone growth (e.g., exostoses), and calcification of ligaments and
tendons. Most cases of crippling fluorosis have occurred in people with a high
occupational fluoride;, exposure (20 to 80 mg/day for 10 to 20 years) or in
populations (not in the United States) with drinking water containing 10 to 40
mg/L fluoride (Federal Register, 1985a; 1985b; World Health Organization,
1984; Hayes, :1982; Mackison et al., 1981; see also Schmidt, 1983;
Anonymous, 1981 a; White, 1980; Smith and Hodge, 1979; Hodge and Smith,
1977). The pain and other symptom^ of crippling fluorosis occur as a result of
abnormal bone growth, which in turn occurs when the normal metabolism and
remodeling of the bone are disrupted by high levels of fluoride. Deposition of
fluoride into the bone, apatite lattice does not in itself cause harm, nor does the
existence of a high fluoride level in the bone. A high bone fluoride level does
indicate that fluoride exposure is or has been high, and high fluoride levels will
disrupt bone metabolism and can thereby eventually cause crippling.
Similar effects on bones and teeth occur in other mammals subjected to
chronic fluoride poisoning, whether from contamination of forage by fluoride.
emissions from nearby factories (Krook and Maylin, 1979a; 1979b; Gruender,
1972a; 1972b; Oelschlaeger et al., 1972), accidental fluoride contamination of
feed (Eckerlin et al., 1986a; 1986b; Parsonson et al., 1975; Hard and Atkinson,
1967a; 1967b; Atkinson and Hard, 1966), or in controlled studies (Grigorenko
et al., 1986; Hard and Atkinson, 1967b; Shupe et al., 1963). Severe symptoms
can result from extremely high fluoride intake; dairy cattle are probably the
most susceptible animals, because of the high calcium turnover and high feed
intake associated with lactation (see Eckerlin et al., 1986b).
Machle and Kitzmiller (1935) reported that no externally obvious adverse
effects were noted in .animals (rabbits, guinea pigs, and Rhesus monkeys)
exposed to 15.2 mg/mS HF for a total of 309 hours (6 to 7 hours per day over
about 10 weeks, followed for up to 8 more months post-exposure). Two guinea
pigs sickened and died after 134 and 160 hours exposure. Both of these
animals showed liver and lung damage (one had pulmonary hemorrhage), and
one had kidney damage. The surviving animals were normal in behavior and
appearance but had slower-than-normal growth rates. Some had lower-than-
normal erythrocyte counts. These animals upon necropsy exhibited varying
degrees of lung, liver, and kidney damage (except the Rhesus monkey, which
had kidney damage only). Stokinger (1949) reported pulmonary damage of
varying degrees in dogs, rabbits, and rats exposed to 3 to 25 mg/m3 F2 for 95
to 176 hours (total, over 3 to 5 weeks) or to 21.1 mg/m3 HF (7.2 mg/m3 for
dogs) for 166 hours (total, over 5 weeks). The dogs also exhibited
degenerative testicular changes. Deposition of fluoride inosseous tissues
occurred with either F2 or HF exposure.
Other effects of chronic fluoride exposure in humans have been reported
occasionally, including pulmonary effects, renal injury, thyroid injury, anemia,
hypersensitivity, and dermatological reactions (Waldbott, 1981; 1980; 1973;
1961; Waldbott and Lee, 1978; McLaren, 1976; Hodge, 1960; Spira, 1944,
cited in Princi, 1960). None of these effects haS been convincingly estab-
lished, particularly for fluoride-concentrations likely to be encountered by the
general public (Federal Register, 1985b; World Health Organization, 1984;
Smith and Hodge, 1979; Safe Drinking Water Committee, 1977; Kaltreider et
al., 1972; Princi, 1960). The U.S. Environmental Protection Agency (1986) has
established an oral Reference'Dose (RfD) for fluoride of 0.06 mg/kg/day for
children, an intake which corresponds to a water fluoride level of 1 mg/L (1
7-5
-------
ppm). Neither dental nor skeletal fluorosis occurs at this level. An inhalation
RfD is not available. :
7.3. Biochemical Effects
Fluoride toxicity involves at least four major effects (Gosselin et al., 1984):
(1) inhibition of enzymes controlling glycolysis or other vital path ways, (2)
hypocalcemia resulting from binding or precipitation of calcium by fluoride, (3)
cardiovascular collapse caused by hypotension and circulatory shock, and (4)
damage to specific organs, primarily the brain and the kidneys.
Fluoride inhibits a number of enzymes, in some cases by complexing with
a metal (e.g., Ca2* or Mg2 + ) associated with the enzyme, in other cases by a
direct action of fluoride (as F or as undissociated HF) on the enzyme itself
(Anonymous, 1985; World Health Organization, 1984; Edwards et al., 1984).
Inhibition of many enzymes will occur at high serum fluoride concentrations, at
least 300 yg/L (World Health Organization, 1984). Serum fluoride concentra-
tions this high generally occur only with acute high fluoride intake (normal
serum fluoride values are muph less than 100 g/L, dependent on the fluoride
content of the drinking water). Among the results of enzyme inhibition by
fluoride are hyperkalemia (increased potassium levels) and metabolic acidosis
(Gosselin et al., 1984; World Health Organization, 1984). Fluoride at lower
concentrations (about 180 ng/L in serum, still much higher than normal) can
activate some other enzymes, most notably adenyl cyclase (World Health
Organization, 1984). Fluoride has been shown to affect the metabolism of
glucose, lipids and cholesterol, and collagen in mammals, as well as the
formation of bones and teeth, and many of these metabolic effects are
probably due to the effects of fluoride on the enzymes involved (see for
instance Den Besten, 1986; Aitbaev, 1984; Dousset et al., 1984a; 1984b;
Drozdz et al., 1984; 1981; Watanabe et al., 1975; serum fluoride levels when
reported were at least 50 ng/L).
Hypocalcemia in cases of acute fluoride poisoning will often result in
tetany-severe involuntary muscle contractions (Gosselin et al., 1984). Many of
the other toxic effects of fluoride (including cardiac arrhythmias and other
effects often associated with acute systemic fluoride poisoning) are thought to
be caused by hypocalcemia (Heifetz and Horowitz, 1986; Kono et al., 1982;
Tepperman, 1980; Abkurah et al., 1972), although the evidence for that is not
entirely clear (Gosselin et al., 1984). Most methods of treatment of HF burns
or NaF poisoning include immediate replacement of calcium and often also of
magnesium (see for instance Bracken et al., 1985; Gosselin et al., 1984;
Trevino et al., 1983; Browne, 1982; Carney et al., 1974; Abkurah et al., 1972;
Klauder et al., 1955).
Cardiovascular collapse :is one of the two most common immediate
causes of death in cases of acute fluoride poisoning (Gosselin et al., 1984).
The hypotension and circulatory shock which are involved result from a
combination of factors such as fluid and electrolyte losses (due to vomiting
and diarrhea or intragastric bleeding) and central vasomotor depression. Brain
damage from acute fluoride poisoning can cause such symptoms as
convulsions, although more commonly lethargy, stupor, and coma are the
result. Respiratory failure (the other leading cause of death in fluoride
poisoning) is thought to be of central nervous system origin (Gosselin et al.,
1984). Renal injury, including transient diabetes insipidus, may also result from
acute fluoride poisoning (it is probably not a major concern in cases of chronic
fluoride exposure), although renal failure does not appear to be a cause of
death (Gosselin et al., 1984). More severe nephrotoxicity, also
7-6
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including diabetes insipidus, may occur from exposure to fluorine-containing
anesthetic agents such as methoxyflurane or enflurane (World Health
Organization, 1984).
7-7
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-------
8. Beneficial Effects
It is generally accepted that fluoride as fluoride ion has a significant
cariostatic (cavity-inhibiting) effect (American Academy of Pediatrics, 1986;
World Health Organization, 1984; Drury et al., 1980), particularly for individ-
uals who receive it during the years of tooth mineralization (prior to age 6).
Fluoride acts systemically in the formation of teeth by being built into the
crystal structure of the enamel, making it harder and more resistant to decay;
it acts topically on erupted teeth by promoting remineralization (American
Academy of Pediatrics, 1986). The acids produced by various oral bacteria
contribute to tooth decay by dissolving enamel; fluoride on the tooth surface
has a bacteriostatic effect, resulting in a decrease in acid production and
ultimately a decrease in tooth decay (Drury et al., 1980).
The most effective way to administer fluoride to the population is via the
water supply, and a number of communities throughout the world now have
artificially fluoridated municipal water supplies. The typical fluoride level for an
artificially fluoridated water source in a temperate climate is 1 mg/L (1 ppm;
Safe Drinking Water Committee, 1977); the recommended fluoride level
changes with the average temperature of a region, due to differences in
expected water consumption (Hayes, 1982). Other means of fluoride delivery
include fluoride-containing tablets, drops, toothpastes, and mouthwashes
(American Academy of Pediatrics, 1986). A few reports suggest that at least
some of the decline in tooth decay attributed to fluoridated water may in fact
be due to other causes, such as changes in immune status, changes in dietary
patterns, and use of topical fluorides (Diesendorf, 1986; Smith, 1986a; 1986c).
The increased bone density found in individuals with a high long-term
fluoride intake suggests a possible use for fluoride in the prevention or
treatment of such diseases as osteoporosis, characterized by an accelerated
decrease in bone mass and strength (Smith, 1986b; World Health
Organization, 1984). Some evidence exists that people living in an area with a
high natural level of fluoride in the water (4 to 8 mg/L) have a lower incidence
of osteoporosis (World Health Organization, 1984). Medical use of high
fluoride doses (50+ mg/day, usually given with calcium and vitamin D
supplements; Drury et al., 1980) is still under investigation (see Dambacher et
al., 1986; Frey, 1986; Smith, 1986b; World Health Organization, 1984; Drury et
al., 1980). In at least some cases, bone density seems to be increased without
a concommitant increase in bone strength-bone formation is stimulated by
fluoride, and fluoride is incorporated into the bone structure, but the overall
bone structure is not entirely normal and is not necessarily stronger (Frey,
1986; Smith, 1986b; see also Dambacher et al., 1986; Snow and Anderson,
1986). Some side effects such as gastrointestinal bleeding (Frey, 1986) or
osteoarticular side effects (Dambacher et al., 1986) can occur from treatment
with large amounts of fluoride, and severe fluorosis can result if a patient with
renal insufficiency is given fluoride for treatment of osteoporosis (Gerster et
al., 1983).
Some epidemiological studies have suggested a correlation between
increased fluoride levels in drinking water (the high level in one study was 2.57
8-1
-------
mg/L) and a decrease in mortality due to heart disease (World Health
Organization, 1984; Luoma et al., 1973). The details of the relationship
between fluoride and cardiovascular disease remain to be worked out,
although one possibility is that fluoride may reduce soft tissue calcification
such as atherosclerosis.
The beneficial effects and the adverse effects of fluoride must be weighed
in determining the optimal fluoride level in drinking water supplies. The most
effective level for the prevention of caries seems to be about 1.0 to 1.2 mg/L;
higher amounts (at least 4 to 5 mg/L) may be necessary for the prevention of
osteoporosis. Some cases of mild dental fluorosis are found when the water
contains 1 to 2 mg/L fluoride; fluorosis is common and occasionally severe at
4 mg/L, Although dental fluorosis is treated as a cosmetic effect and not a
health effect, some people do consider it objectionable (Federal Register
1985b). • '
Fluoride is usually added to water in the form of sodium fluoride (NaF),
sodium fluosilicate (Na2SiF6), fluosilicic acid (H2SiF6), or ammonium
fluosilicate [(NH4)2SiF6] (Safe Drinking Water Committee, 1977). Sodium
fluoride, stannous fluoride (SnF2), acidulated phosphate fluoride, and
monofluorophosphate are the fluorides most commonly added to dentifrices
and mouthwashes (Heifetz and Horowitz, 1986). Sodium fluoride is also the
main fluoride used in treatment of osteoporosis (Frey, 1986; Smith, 1986b),
although at least one fluorine-containing organic compound, niflumic acid (2-
[3-(trifluoromethyl)anilino]nicotinic acid), has been suggested as a possible
drug for this use (Meunier et al., 1980). Hydrogen fluoride is not used in these
capacities, although it is important as an intermediate in the production of
some of these other fluoride compounds.
8-2
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9. References
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Blanks, R. V. (1972) Acute sodium, flouride poisoning. JAMA J. Am. Med.
, Assoc. 222:816-817.
Ahlborg, G.; Hogstedt, C.; Sundell, L; Aman, C.-G. (1981) Laryngeal cancer
and pickling house vapors. Scand. J. Work Environ. Health 7: 239-240.
Aitbaev, T. Kh. (1984) [Changes in various indicators of lipid metabolism
during isolated and combined exposure to hydrogen flouride, sulfur
dioxide and hydrogen sulfide in various concentrations]. Gig. Tr. Prof.
Zabol. (6): 16-19.
Alary, J.; Bourbon, P.; Balsa, C.; Bonte, J.; Bonte, C. (1981) A field study of
the validity of static paper sampling in flouride pollution surveys. Sci. Total
' Environ. 22:, 11-18
American Academy of Pediatrics, Committee on Nutrition.,(1986) Flouride
supplementation. Pediatrics 77: 758-761.
American Conference of Governmental Industrial Hygienists. (1986) TLV's:
threshold limit values for chemical substances in the work environment
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Amoore, J. E.; Hautala, E. (1983) Odor as an aid to chemical safety: odor
thresholds compared with threshold limit values and volatilities for 214
industrial chemicals in air and water dilution. JAT J. Appl. Toxicol. 3: 272-
290.
Anonymous. (1981 a) Chronic flourosis. Br. Med. J. 282: 253-254.
Anonymous. (1981b) Hydroflouric acid. Dangerous Prop. Ind. Mater. Rep. 1(6):
64-66.
Anonymous. (1985) How flouride might damage your health. New Sci. (1445):
20.
Anonymous. (1986) Flouride in food and water. Nutr. Rev. 44: 233-235.
Atkinson, F. F. V.; Hard, G. C. (1966) Chronic flourosis in the guinea-pig.
Nature (London) 211: 429-430.
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Baltazar, R. F.; Mower, M. M.; Reider, R.; Funk, M.; Salomon, J. (1980) Acute
fluoride poisoning leading to fatal hyperkalemia. Chest 78: 660-663.
Barnard, W. R.; Nordstrom, D. K. (1982) Flouride in precipitation - II.
Implications for the geochemical cycling of flourine. Atmos Environ 16'
105-111.
Bartels, O. G. (1972) An estimate of volcanic contributions to the atmosphere
and volcanic gases and sublimates as the source of the radioisotopes
, 35S, sap, and 22Na Hea|th phys 22. 337.392
Baxter, P. J.; Stoiber, R. E.; Williams, S. N. (1982) Volcanic gases and health:
Masaya Volcano, Nicaragua [letter]. Lancet (8290): 150-151.
Boscak, V. (1978) Screening study on feasibility of standards of performance
for hydroflouric acid manufacture. Research Triangle Park, NC: U. S.
Environmental Protection Agency, Office of Air Quality Planning and
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