NATIONAL AMBIENT AIR QUALITY OBJECTIVES FOR

HYDROGEN FLUORIDE (HF)

SCIENCE ASSESSMENT DOCUMENT

A Report by the CEPA/FPAC Working Group on

Air Quality Objectives and Guidelines
ACKNOWLEDGEMENTS

This report is published under section 8 of the Canadian Environmental Protection Act (CEPA).

Any inquiries concerning this publication or requests for copies should be directed to either of

the following officials:

Director

Science Assessment and

Policy Integration Division

Atmospheric Environment Service

Environment Canada

4905 Dufferin Street

Toronto, Ontario M3H 5T4

Director

Bureau of Chemical Hazards

Environmental Health Centre

Health Canada

Tunney's Pasture

Ottawa, Ontario K1A 0L2

This report has been prepared by the following people:

M. Bourgeau, Health Canada, Environmental Health Directorate

D. Clapin, Health Canada, Environmental Health Directorate

K. Foster, Alberta Environmental Protection, Environmental Assessment Division

R. Jones, Ontario Ministry of Environment and Energy, Phytotoxicology Section

M. Prior, Alberta Ministry of Health, Environmental Health Services Branch

M. Shepherd, Environment Canada, Atmospheric Environment Service

P. Walsh, Quebec Environment

Final technical editing and desktop publishing by Astroff Corkum Ross Associates Inc.

July 1996

ISBN 0-662-25641-7

Catalogue En42-17/6-1997E
Science Assessment Document for HF i CEPA/FPAC WGAQOG July 1996

TABLE OF CONTENTS

FIGURES AND TABLES ............................................................................................................iii

PREFACE .................................................................................................................................. v

1 INTRODUCTION...................................................................................................................1

2 RECOMMENDED REFERENCE LEVELS FOR HYDROGEN FLUORIDE...........................3

2.1 Rationale for the Reference Levels for Gaseous Hydrogen Fluoride (HF).....................4

2.2 Summary of Animal Effects, and the Rationale for Limiting Fluoride Accumulation

in Forage .......................................................................................................................6

2.3 Summary of Human Health Effects ...............................................................................7

3 BACKGROUND ....................................................................................................................9

3.1 Physical and Chemical Characteristics of Hydrogen Fluoride........................................9

3.2 Sources .........................................................................................................................9

3.3 Monitoring Methodologies............................................................................................10

3.4 Environmental Levels in Canada .................................................................................14

3.5 Ambient Air Objectives and Standards in Other Jurisdictions ......................................14

4 EFFECTS ON VEGETATION .............................................................................................19

4.1 Effects of Fluorides on Vegetation...............................................................................19

4.2 Fluoride Accumulation in Vegetation ...........................................................................21

4.3 Canadian Case Studies ...............................................................................................24

4.3.1 Phosphorus Reduction Long Harbour, Newfoundland ......................................24

4.3.2 Phosphorus Fertilizer Production Port Maitland, Ontario...................................26

4.3.3 Aluminum Reduction Cornwall Island, Ontario ..................................................26

4.3.4 Aluminum Reduction Arvida, Quebec................................................................27

4.3.5 Aluminum Manufacturing Kitimat, British Columbia ...........................................28

4.3.6 Aluminum Engine Casting Windsor, Ontario .....................................................28

4.3.7 Uranium Processing Port Hope, Ontario ...........................................................28

4.3.8 Tile Manufacturing Niagara, Ontario..................................................................29

4.3.9 Brick Manufacturing Southern Ontario ..............................................................29

4.3.10 ........................................................... Fibreglass Manufacturing Guelph, Ontario 29

4.3.11 ........................................................................ Oil Refining Mississauga, Ontario 30

4.4 Interactive Effects of HF with Other Gaseous Pollutants .............................................30
Science Assessment Document for HF ii CEPA/FPAC WGAQOG July 1996

5 EFFECTS ON LIVESTOCK AND WILDLIFE ......................................................................33

5.1 Pharmacokinetics ........................................................................................................33

5.2 Pharmacodynamics .....................................................................................................34

5.2.1 Acute Toxicity ....................................................................................................34

5.2.2 Chronic Toxicity.................................................................................................35

5.2.3 Developmental Toxicity, Reproductive Effects and Carcinogenesis..................35

5.2.4 Fluorides............................................................................................................35

5.3 Conclusion...................................................................................................................37

6 EFFECTS ON EXPERIMENTAL ANIMALS ........................................................................39

6.1 Acute Toxicity ..............................................................................................................39

6.2 Short-term Toxicity.......................................................................................................41

6.3 Long-term Toxicity and Carcinogenicity Studies ..........................................................43

6.4 Reproductive Toxicity, Teratology and Genotoxicity Studies .......................................45

6.5 Conclusion...................................................................................................................45

7 EFFECTS ON HUMAN HEALTH ........................................................................................47

7.1 Pharmacokinetics ........................................................................................................47

7.1.1 Absorption .........................................................................................................47

7.1.2 Distribution ........................................................................................................48

7.1.3 Excretion ...........................................................................................................50

7.1.4 Monitoring Exposure to Gaseous Fluoride by Pharmacokinetic Parameters.....52

7.2 Pharmacodynamics .....................................................................................................53

7.3 Effects in Humans .......................................................................................................56

7.3.1 Acute and Short-term Health Effects.................................................................56

7.3.2 Chronic Health Effects.......................................................................................58

7.4 Summary of Health Effects of Inorganic Fluorides as Reported by CEPA...................68

7.5 Human Exposure Assessment.....................................................................................70

7.6 Summary and Conclusion............................................................................................72

8 REFERENCES ...................................................................................................................75

8.1 Comprehensive Surveys..............................................................................................75

8.2 Literature Cited ............................................................................................................75

Appendix HF Reference Dose Database ................................................................................97
Science Assessment Document for HF iii CEPA/FPAC WGAQOG July 1996

FIGURES

Fig. 1 Regression analysis of HF-exposure data......................................................................5

Fig. 2 Average monthly ambient HF concentration.................................................................16

Fig. 3 HF fluoridation rate monthly averages for Ontario, 1991–92........................................17

TABLES

Table 1 Reference levels for HF in ambient air, and maximum level of accumulated fluoride

in vegetation .................................................................................................................3

Table 2 Estimates of HF air emissions ....................................................................................10

Table 3 Capacity of Canadian aluminum producers, 1992......................................................11

Table 4 Locations of coal-burning electricity generating utilities in Canada ............................12

Table 5 Ambient HF concentration ranges at selected Canadian sites, 1980–91 ...................15

Table 6 Ambient air quality standards and objectives for gaseous fluorides (μg m-3),

and fluoride levels in vegetation (μg g-1 DW), in other jurisdictions ............................18

Table 7 Susceptibility of animals to fluoride by ingestion ........................................................37

Table 8 Estimates of NOAEL and LOAEL for mice and rats ...................................................37

Table 9 Estimated upper bound of daily intake of gaseous fluorides ......................................71
Science Assessment Document for HF iv CEPA/FPAC WGAQOG July 1996
Science Assessment Document for HF v CEPA/FPAC WGAQOG July 1996

PREFACE

The Canadian Environmental Protection Act

(CEPA), passed into law in 1988, replaces

and builds upon the Clean Air Act and the

Environmental Contaminants Act. The

opening statement of the Act declares that

"the protection of the environment is

essential to the well-being of Canada."

CEPA allows the federal government to

assess substances and control their impact

through national environmental quality

objectives, guidelines, codes of practice,

and/or regulations.

Provincial governments have the primary

responsibility in many areas of air pollution

control, with federal actions integrated with

those of the provinces. The CEPA

Federal/Provincial Working Group on Air

Quality Objectives and Guidelines, consisting

of representatives of federal, provincial and

territorial departments of environment and

health, reviews and recommends ambient air

quality objectives.

Canada's National Ambient Air Quality

Objectives prescribe targets for air quality,

measured at the relevant receptor (persons,

plants, animals, materials). Development of

objectives follows a process which integrates

the review of physical and chemical

properties and sources; environmental,

animal and human health effects;

environmental and human exposure

assessment within a framework of risk

assessment. These targets may incorporate

some element of cost-benefit-risk, reflecting

a philosophy of environmental health

protection and long-term risk reduction while

recognizing technological and economic

limits. The broad range of potential

responses by the population, the

ecosystems, and organisms in the

environments are considered. However,

given the range of these sensitivities, the

resulting objectives may not protect

everyone. A document outlining the process

followed in reviewing and interpreting

scientific information leading to the

recommendation of objectives is published

separately.1

The levels recommended as a result of this

process accommodate two tiers, defined as

follows:

• The Reference Level is a level above

which there are demonstrated effects on

human health and/or the environment. It

provides a scientific basis for establishing

goals for air quality management.

• The Air Quality Objective represents the

air quality management goal for the

protection of the general public and the

environment in Canada. It is a level based

upon consideration of scientific, social,

economic and technological factors.

The process of establishing air quality

objectives is a dynamic and continuous one.

This document recommends Reference

Level(s) for hydrogen fluoride.

The air quality objectives are established to

provide the current state of knowledge about

an air-quality parameter, a uniform scale for

assessing the quality of air in all parts of

Canada, and guidance to governments for

making risk-management decisions such as

planning control strategies and setting local

standards.

1 CEPA/FPAC, Working Group on Air Quality Objectives and Guidelines (1996) Protocol for the Development of National Ambient Air

Quality Objectives
Science Assessment Document for HF vi CEPA/FPAC WGAQOG July 1996

It is recognized that not all locations in

Canada will meet these air quality objectives

immediately, or at all times, and that priority

given to meet these values may be based

on factors such as available control

technology, costs, benefits, and the degree

to which the recommended levels are

exceeded. The expectation is that strategies

be put into place to reduce ambient air

concentrations to below these targets as

soon as practicable. The principles of

continuous improvement and nondegradation of environmental quality are

advocated.
Science Assessment Document for HF 1 CEPA/FPAC WGAQOG July 1996

1 INTRODUCTION

This document reviews the scientific

literature regarding the effects of gaseous

fluorides on vegetation, animals and

humans. The available data have been

compiled, and studies that provide

information which can be used to derive a

reference level for gaseous HF have been

extracted and evaluated. This evaluation

provides the basis for the proposal of a

reference level for each of four time periods.

Each reference level represents an ambientair HF concentration above which an effect is

likely to occur. Information on gaseous HF

effects on humans and animals is also

provided in this document to assist in

assessing the impact of HF in situations of

extreme exposure.

While sufficient data is available to support the

derivation of a reference level for each of the

four periods, the number of species tested

under conditions expected to occur in Canada

is limited. Additionally, there is an indication

that some plants of economic (grapevine,

peach) or natural (wild grape) importance in

Canada may be affected at the proposed

levels; however, direct evidence is lacking.

Further research will determine if these levels

require revision. It is recommended that

monitoring of ambient HF levels be conducted

in those areas in which potentially sensitive

species grow or are cultivated (e.g., vineyards,

peach orchards), and which are located near

sources of airborne fluorides. Derivation of an

Air Quality Objective for HF should await the

completion of these additional studies and

monitoring efforts.

Fluorides have two different environmental

effects. Fluorides accumulate and cause

damage in vegetation; this is the primary

environmental effect. The period during

which plants are exposed to HF, the

concentration of HF in the air, and intervals

between HF exposures, affect the extent of

accumulation and damage. For the

protection of vegetation from HF damage,

reference levels for each of 1-, 7-, 30- and

90-day periods are proposed in this

document.

The second environmental effect is the effect

of fluorides accumulated in vegetation on

herbivores (livestock and wildlife). Fluorides

of all forms, both within the leaf and adhering

to the exterior plant surface, contribute to

fluoride toxicity. Additionally, some plants

may accumulate levels of fluoride which are

harmful to herbivores, but which are not toxic

to the plants. Therefore, there is no means

by which the proposed HF reference levels

can be used to estimate fluoride levels in

forage plants, or that can be considered

adequate for the protection of herbivores.

Consequently, for the protection of wildlife

and livestock, a reference level for total

fluoride content in plants is presented.

Although not used in the derivation of the

reference levels, data regarding the effects

of fluorides on animal and human health are

included in this document. This material

provides information on multi-pathway

exposure routes as well as information about

acute HF exposures.

This document represents an expert

synthesis of the available scientific literature.

A listing of comprehensive scientific reviews

that provide additional details in support of

this synthesis is given in References.

Unless explicitly stated otherwise, all units

in this document are given as micrograms of

hydrogen fluoride per cubic metre (μg HF m-3)
Science Assessment Document for HF 2 CEPA/FPAC WGAQOG July 1996

for ambient concentration levels, or as micrograms of fluoride per gram dry weight

(μg F g-1 DW) for fluoride accumulation in

forage.
Science Assessment Document for HF 3 CEPA/FPAC WGAQOG July 1996
Science Assessment Document for HF 4 CEPA/FPAC WGAQOG July 1996

2 RECOMMENDED REFERENCE

LEVELS FOR HYDROGEN FLUORIDE

The recommended reference levels for

hydrogen fluoride (HF) in ambient air are

presented in table 1. Also presented is the

recommended reference level for maximum

fluoride accumulation in forage. These

concentrations represent the concentrations

of HF in ambient air, and fluoride

accumulation in forage, above which an

effect on vegetation, and on animals which

feed on this vegetation, may be expected

from airborne fluorides.

Table 1 Reference levels for HF in ambient air, and maximum level of accumulated

fluoride in vegetation

Averaging time

Level 24 hours 7 days 30 days 90 days Receptor

Reference level

(μg HF m-3)

1.1 0.5 0.4 0.4 Vegetation

Vegetation fluoride level

(μg F - g-1 DW)

30 Livestock and wildlife

Hydrogen fluoride is the most prevalent

gaseous fluoride. There is no phytotoxic

information available for the covalently

bonded gaseous fluorides, SF6 or CF4.

These covalently bonded gases do not

dissociate to form the fluoride ion (as does

HF) and subsequent phytotoxic impacts are

expected to be negligible.

The gaseous HF concentration in ambient air

varies from 0.01 to 1.65 μg m-3 in Canada

and the U.S.A. Levels are higher adjacent to

facilities which emit HF. Ambient levels range

from 100 to 10,000 times less than the

estimated effect level derived from human

studies. Children, people with impaired

kidney function, industrially exposed

workers, and persons living in the vicinity of

a point source of fluoride emissions may be

at somewhat greater risk than the general

population, though all such groups are

expected to be exposed to HF well below the

effects level. Human studies revealed a

NOAEL (No Observable Adverse Effect

Level) of 0.9 mg m-3 HF for skin and eye

irritation and a NOAEL of 2.1 mg m-3 for

irritation of the respiratory tract. The odour

threshold ranged from 0.02 to 0.22 mg m-3.

HF gas is a potent acute toxicant when

animals are exposed to large quantities

acutely via the respiratory route. The

chemical properties of the compound

account for its pharmacodynamic properties:

it dissociates when mixed with water to form

a strong acid resulting in burns, and it binds

to calcium resulting in sequestration of

calcium and alteration of bone calcium

(chronic exposure). From the weak chronic

study data, it appears as though a continual

exposure to mammals should not exceed

7 mg m-3.

Science Assessment Document for HF 4 CEPA/FPAC WGAQOG July 1996

2.1 RATIONALE FOR THE

REFERENCE LEVELS FOR

GASEOUS HYDROGEN

FLUORIDE (HF)

Based on the literature review presented in

the remainder of this document, it is

concluded that vegetation is more sensitive

than human health to the toxic effects of

fluorides. Therefore, the reference levels are

based on the results from investigations into

the effects of HF on plants. Experimental

data from 13 investigations into the effects of

HF on plants, representing 32 separate

effects results, have been judged acceptable

for use (see appendix). This data set

includes 18 points from studies using plants

of horticultural importance, 10 from studies

using agricultural species, and 4 from studies

of effects on forest (conifer) species. There

is insufficient data within each of these

classes to derive separate reference levels

for each class.

Coulter et al. (1985) found that injury in

Gladiolus had a closer relationship to the HF

dose than to HF concentration, duration of

exposure, or frequency of exposure. For this

reason, each selected HF treatment was

converted to a dose (concentration multiplied

by the duration of exposure), which has the

units μg days m-3. This normalization assists

in the comparison of studies.

Since the data were selected on the basis of

expert judgement, and because many of the

studies did not present a measure of

variability or analysis of normality associated

with the data, the data set of 32 points does

not satisfy many assumptions required for

analysis by most statistical methods. Curvefitting techniques may be useful in making

sense of the data; however, choice of the

type of curve (quadratic, polynomial) is not

obvious, and in fact, none of the curves (up

to a third-order polynomial) adequately

described the data, and none gave an

equation from which reference levels

considered protective could be calculated.

Although the data set likely does not meet

the requirements for statistical treatment

(random, normal distribution), statistical

methods may be used as tools to help derive

the reference levels. The results of such

analyses must be evaluated in the context of

what is known about the effects of HF on

plants, and the reference levels calculated

using such methods should be examined

very carefully to determine if they represent

an acceptable level of protection expected

from the reference levels. The question to be

answered is: Do the reference levels

calculated using mathematical or statistical

methods adequately describe a relationship

between the duration of HF exposure and

the dose (or concentration) above which an

effect of HF on plants may be expected?

Regression analysis, including a calculation

of confidence intervals, was chosen as the

best tool to assist in the derivation of the

reference levels. The results of this analysis

are presented in fig. 1; it is based on data

selected from the scientific literature shown

in the appendix. It is important to note that

some of the data points presented in fig. 1

should carry greater weight than others,

based on experimental and statistical rigour

included in the study. However, since

variability associated with each of the points

is not given, it is not possible to give greater

weight to some of the points. Given this

deficiency, the lines and the reference levels

derived from them must be evaluated

carefully.
Science Assessment Document for HF 5 CEPA/FPAC WGAQOG July 1996

The reference levels were calculated from

the lower confidence level for 1-, 7-, 30- and

90-day periods using equations presented by

Steel and Torrie (1980) for calculating

confidence intervals. The levels are

presented in table 1.

Evaluation of these levels must include an

examination of the points which fall below

the lower limit, since they represent

instances where plants may be damaged by

HF at doses and concentrations below the

recommended reference levels. Seven data

points lie below this line (fig. 1); these points

were extracted from six studies. An

assessment of each of these studies is

required to determine if the reference levels

derived from this line are protective.

Leaf injury in Gladiolus following HF

exposure represents two of the seven points.

Adams et al. (1956) reported that a small

amount of leaf injury (0.7% of the leaf length

was necrotic) was observed at 0.85 μg m-3

when treated in small fumigation

greenhouses for 24 hours. Treatment with

2.10 μg m-3 for 1 day per week for 7 weeks

caused burning on Gladiolus leaf tips

(McCune et al., 1966). While Gladiolus is

generally believed to be the most sensitive

species in terms of response to HF

exposure, several of the data points well

above the 95% confidence level were

extracted from Gladiolus studies. The small

amount of leaf damage observed in these

studies is judged to be insufficient cause to

modify the reference levels calculated from

the line representing the 95% confidence

interval.

The third point below the 95% confidence

levels was extracted from MacLean et al.

(1982). Leaf necrosis was observed

Fig. 1 Regression analysis of HF-exposure data selected from the scientific

literature shown in the appendix. The upper and lower 95% confidence

levels are indicated by hatched lines. The lower 95% confidence level was

used to calculate the reference levels for 1, 7, 30 and 90 days.
Science Assessment Document for HF 6 CEPA/FPAC WGAQOG July 1996

following treatment of Jerusalem cherry with

0.90 μg m-3 for 24 hours in the dark, followed

by a light period without HF. Damage only

occurred following transfer to the light. Dark

exposure for a duration approximating a

Canadian summer night (ca. 6 to 8 hours)

was not investigated. This type of exposure

is artificial, and while it does add to the

understanding of HF responses in plants, it is

not appropriate to lower the calculated

reference levels based on this study.

First injury on grape leaves was observed at

0.17 μg m-3 after 99 continuous days of

fumigation, and at 83 days following

continuous treatment with 0.27 μg m-3

(Murray, 1984). This is the time to first

observable injury on the leaves, and fruit

yield and quality were not affected. These

effects are not sufficient to modify the

interpretation of the data represented by the

95% line.

Peach tree growth was reduced by about

25%, with a minor amount of leaf necrosis, at

0.34 μg m-3 for 110 days; this point falls just

below the 95% confidence level (Hill and

Pack, 1983). This is a substantial effect, and

since peaches are grown in Canada, it must

be seriously considered. However, the point

is very close to the 95% line; adjusting the

line downward to include this study would

cause the reference levels to be lowered by

a very small amount. The effect represented

by this point (Hill and Pack, 1983), and it's

proximity to the line used to derive the

reference level, makes it apparent that

further work on the effects of HF on peach

trees is required.

Peanut yield was reduced when treated with

0.26 μg m-3 HF for 105 days in the field in

open-top chambers (Murray and Wilson,

1990). This study used levels of HF which

are likely to occur in the environment, and

was conducted under as close to natural

conditions as are technically possible at this

time. While peanut does not represent a crop

of importance in Canada, yield reductions in

this species under these conditions raise the

possibility that other cultivated crops,

particularly related legumes, may be similarly

affected.

Solberg et al. (1955) reported that a

concentration of 0.51 μg m-3 for 24 hours

injured one in five ponderosa pine trees

(see appendix). While this study may

indicate a level of HF below the proposed

reference levels that could cause damage,

Solberg et al. (1955) reported only nominal

HF concentrations; actual treatment

concentrations were not measured or

reported. Without this information, the

validity of the data cannot be evaluated, and

this study was not used in the derivation of

the reference level as presented in fig. 1.

Thus, while the regression analysis

presented in this section does not satisfy

statistical requirements, the analysis was

used as a tool to assist in the evaluation of

currently available scientific data. Based on

this evaluation, the recommended reference

levels are judged to represent an acceptable

level of protection.

2.2 SUMMARY OF ANIMAL

EFFECTS, AND THE

RATIONALE FOR LIMITING

FLUORIDE ACCUMULATION IN

FORAGE

Minimal data is available from which to

assess the effects of gaseous HF on

livestock, wildlife or experimental animals

(Rousseaux, 1995). Due to scarcity of data

collected for a few exposure periods, some
Science Assessment Document for HF 7 CEPA/FPAC WGAQOG July 1996

of which are gleaned from older studies of

varying analytical precision or accuracy, it is

not appropriate to recommend exposure

guidelines to protect animal health. HF is a

potent, acute toxicant when animals are

exposed to large quantities acutely via the

respiratory route. Since HF rapidly becomes

a fluoride salt, the majority of the toxicity

issues can be considered under the

evaluation of the toxicity of fluorides.

Generally, HF toxicity can be attributed to

the corrosive action of hydrofluoric acid,

sequestering of free calcium to form calcium

fluoride, and the alteration of the

hydroxyapatite crystal in osseous materials.

The recommended reference levels for HF

are approximately two orders of magnitude

less than those observed to have adverse

effects on animals.

Fluoride uptake by livestock and wildlife via

the accumulation of fluoride in forage may be

of concern near sources of fluoride

emissions. The accumulation of fluoride by

vegetation is dependent upon the amount of

ambient fluoride (gaseous or particulate), the

pattern of exposure, the plant species and

the environment before, during and following

exposure. It is not possible to calculate

previous ambient-air HF levels from

vegetation fluoride content, although

vegetation fluoride monitoring can be used to

assist in the diagnosis of animal injury and in

the identification of fluoride sources.

Concentrations of 20 to 40 μg F- g-1 dry

weight forage have been observed to cause

adverse effects in livestock (Suttie, 1969;

Joseph-Enriquez et al., 1990). Various

experiments demonstrated that different

types of forage could accumulate up to

40 μg g-1 dry weight fluoride when they were

exposed to 0.33 to 1.3 μg m-3 fluorides for

30 days (National Research Council, 1971).

The reference level recommended in table 1

(0.4 μg m-3 for 30 days) is at the low end of

this range. A study by Davison and

Blakemore (1976) on forage exposed to

0.54 μg m-3 fluorides for 30 days resulted in

a fluoride concentration of 33 μg g-1 dry

weight in washed forage. The recommended

air quality objectives for HF will not likely

result in the accumulation of fluorides in

forage from HF in amounts which would

induce fluorosis in livestock and wildlife. It is

important to note that the measurement of

forage fluoride content should be performed

on unwashed forage samples to ensure that

the contribution of particulate forms of

fluoride, as well as any other fluoride

adhering to the exterior surfaces of the plant,

are included in the analysis, since they are

metabolically active and can contribute to

fluorosis in animals.

A reference level of 30 μg F- g-1 dry weight

forage is recommended for the protection of

wildlife and livestock from fluorosis

originating from fluoride accumulation in

forage (table 1).

2.3 SUMMARY OF HUMAN HEALTH

EFFECTS

Inhaled fluorides are rapidly absorbed in the

upper respiratory tract; close to 100% of

inhaled HF is absorbed. The fate or effects

of absorbed fluorides are essentially

independent of the fluoride source or the

route of exposure. About 50% of absorbed

fluoride is retained in the body.

Approximately 99% of the fluoride in the

body is found in the skeleton, the remainder

is distributed in soft tissue.

Studies in humans revealed a NOAEL

(No Observable Adverse Effect Level) of

0.9 mg m-3 airborne HF for skin and eye

irritation and a NOAEL of 2.1 mg m-3 for
Science Assessment Document for HF 8 CEPA/FPAC WGAQOG July 1996

irritation of respiratory tract. The odour

threshold ranged from 0.02 to 0.22 mg m-3.

Clinical studies and most epidemiological

studies on the inhalation of fluorides were

not adequately designed to derive a NOAEL

for systemic effects, or to identify clear effect

level. Often the individual exposure of

fluorides by the ambient air is not monitored.

In workplace studies, people are exposed to

many other potentially toxic compounds in

addition to gaseous and particulate fluorides

in the ambient air. Cross-sectional studies

were too small in number. Only a few chronic

epidemiological studies provide some

quantitative information on the exposure

level indicative for toxic effects on skeleton

(fluorosis and osteosclerosis) and the

respiratory tract. However, a distinct NOAEL

for airborne fluoride including HF could not

be established. From the indicative estimates

it can be concluded that levels below 1.78 to

2.5 mg m-3 airborne HF for an exposure time

of 8 hours are generally considered not to

cause skeletal alterations. Pulmonary effects

are reported to appear in children above

200 μg F m-3 for gaseous fluoride (and

300 μg F m-3 for particulate fluoride). For

workers being exposed to multiple air

pollutants, it is impossible to establish a

NOAEL for gaseous fluorides. In humans, no

effects of chronic exposure to airborne HF

on kidneys, brain, thyroid, haematopoietic

system, or sensitivity were convincingly

established at exposure levels to be

realistically feasible in ambient air or causing

skeletal alterations or effects on the

respiratory tract. No specific epidemiologic

data on carcinogenic effects of airborne

fluoride were available.

The ambient air concentration of gaseous

fluoride varies from 0.01 to 1.65 μg m-3 in

Canada and the U.S.A.. The exposure levels

in most parts of Canada are below 5 μg m-3.

Ambient exposures range from 100 to

10,000 less than the estimated effect level

derived from human studies. Children,

people with impaired kidney function,

industrially exposed workers, and persons

living in the vicinity of a point source of

fluoride emissions may be at somewhat

greater risk than the general population,

though all such groups are expected to be

well below the effects level.
Science Assessment Document for HF 9 CEPA/FPAC WGAQOG July 1996

3 BACKGROUND

Fluorine (F2) is a halogen that exists as a gas

under standard conditions. It is a light yellowgreen, pungent, acrid gas. Fluorine is too

reactive to be found in the environment in its

elemental state and exists as inorganic

fluoride (F-, free ionic, matrix-bound, and

ionically and covalently bonded in inorganic

compounds) or organic fluoride (covalently

bound in organic compounds). Fluorides

exist in the atmosphere as gases and

particulates. Gaseous fluorides at ambient

temperatures and pressures are hydrogen

fluoride (HF), sulphur hexafluoride (SF6) and

carbon tetrafluoride (CF4). Polymeric

fluorides are H3F3, H4F4, silicon fluoride

(SiF4), and hydrofluorisilic acid (H2SiF6).

Common particulate fluorides are aluminum

fluoride (AlF3), cryolite (Na3AlF6), fluoropatite

(CaF2•3Ca3P2O8), calcium fluoride (CaF2)

and sodium fluoride (NaF).

Atmospheric fluorides affect the growth,

development and productivity of vegetation.

The effects of gaseous fluorides are more

phytotoxic than those of particulate fluorides

because they are more readily absorbed by

vegetation.

3.1 PHYSICAL AND CHEMICAL

CHARACTERISTICS OF

HYDROGEN FLUORIDE

HF is the most reactive form in which fluorine

exists in the environment. It is a colourless,

pungent, acrid gas at room temperature. It is

highly soluble in many organic solvents and

water, where it forms hydrofluoric acid.

Approximately 75% of the atmospheric

gaseous fluoride exists as HF. Combined

with water, HF vapour forms an aerosol or

fog of aqueous hydrofluoric acid. Wet

deposition is the primary removal mechanism

of HF from the atmosphere.

3.2 SOURCES

The major natural source of gaseous fluoride

(primarily as HF) emissions are volcanoes.

Other sources of inorganic fluorides to the

environment are mineral weathering and

from marine aerosols. Global releases of HF

from volcanic sources are estimated to be 6

to 6,000 ktonnes, 10% of which are injected

into the stratosphere. Much of the volcanic

HF is removed by precipitation. The primary

anthropogenic emission sources in Canada

are aluminum smelting operations (~75%),

coal-burning facilities (~10%), and chemical

production (~6%). Table 2 summarizes

estimated HF emissions in Canada.

Canadian consumption of HF is ~70 ktonnes.

HF is manufactured from calcium fluoride

and used in the production of synthetic

cryolite, aluminum trifluoride, motor gasoline

alkylates, chlorofluorocarbons, uranium

tetrafluoride and uranium hexafluoride.

Canadian aluminum production utilizes the

synthetic cryolite produced in Canada.

There are 11 primary aluminum producers in

Canada: one in Kitimat, British Columbia,

and 10 in Quebec (table 3). All of the

aluminum in Canada is produced by the HallHeroult process (Environment Canada,

1976, 1994): the electrolytic dissociation of

alumina (Al2O3) dissolved in a molten cryolite

(Na3AlF6) bath. Electrolysis occurs in a

carbon crucible (acting as the cathode)

within a steel shell. Carbon anodes are

suspended above the cell and the aluminum

metal forms at the cathode in the bottom of
Science Assessment Document for HF 10 CEPA/FPAC WGAQOG July 1996

the crucible. Oxygen gas is released at the

anode, burning the carbon anode. The

electrolysis cell operates continuously, and

fresh alumina and cryolite are added to the

cell as required. Hoods over the cell collect

the volatilized fluoride, hydrofluoric acid

vapours and particulate silicon fluoride.

These gases are scrubbed prior to discharge

into the atmosphere. The control efficiency

for volatile fluoride emissions varies from

75% to 99%.

Table 2 Estimates of HF air emissions

Source sector Air releases (tonnes year-1) Relative Contributions

Biogenic

Volcanic emissions 0.06–6 × 106100

Anthropogenic

Primary aluminum producers 4,063.4 75

Coal-burning utilities 543.1 10

Chemical producers 305.3 6

Steel producers 238.9 4

Phosphate fertilizer producers 107.6 2

Magnesium producers 100 2

Other 51.3 1

Total 5,409.6 100

Source: Environment Canada, 1994

HF is also emitted from coal-burning utilities

(table 4). The primary coal types used in

Canada are bituminous and sub-bituminous.

A small amount of lignite coal is also burned.

The HF emission factors for bituminous and

lignite coals are 0.12 kg HF Mg-1 coal and

0.01 kg HF Mg-1 coal, respectively (Emmel

et al., 1989).

3.3 MONITORING

METHODOLOGIES

HF is not monitored by Environment Canada

or the provinces on a continuous basis.

Measurements are made on a site specific

basis, typically to characterize the impact of

a local source on surrounding areas or to

provide information on a specific area of

concern as identified by total ambient

fluoride
Science Assessment Document for HF 11 CEPA/FPAC WGAQOG July 1996

monitoring. The two most prevalent methods

used in Canada for monitoring total ambient

fluorides are the passive and the dual-tape

sampler methods.

Passive techniques do not differentiate

between gaseous and particulate forms of

ambient fluorides, but provide information on

overall fluoridation rates. This cannot be

directly related to vegetation impact or to the

accumulation of fluoride in forage. Passive

methods provide an inexact quantification of

HF since fluoride collection depends upon

local meteorological conditions, which control

the flux of fluoride to and from the collecting

surface, and retention of HF on the sampler

surface. Error rates of up to 50% have been

reported (Ontario Ministry of the

Environment, 1979). Passive techniques are

inexpensive and robust, and do serve to

provide a longterm record of total ambient fluoride levels.

Currently, passive techniques are used to

assess general dispersion conditions around

a source, and to locate a potential area of

concern which may then be examined using

an HF-specific methodology.

Table 3 Capacity of Canadian aluminum producers, 1992

Producers Plants Capacity (tonnes)

Alcan Smelters and Chemicals Ltd. Kitimat, B.C. 272,000

Isle-Malign, Alma, Que. 73,000

Beauharnois, Que. 48,000

Grande-Baie, Que. 180,000

Arvida, Jonquière, Que. 232,000

Laterrière, Que. 204,000

Shawinigan, Que. 84,000

Aluminerie de Bécancour Inc. Bécancour, Que. 360,000

Canadian Reynolds Metals Company

Ltd.

Baie-Comeau, Que. 400,000

Aluminerie Lauralco Inc. Deschambault, Que. 215,000

Aluminerie Alouette Inc. Sept-Îles, Que. 215,000

Total 2,283,000

Source: Natural Resources Canada, 1995
Science Assessment Document for HF 3-12 CEPA/FPAC WGAQOG July 1996

In order to determine whether or not a region

may be exceeding the recommended air

quality reference levels for HF or ambient HF

objectives, one of the HF-specific

methodologies must be used (discussed at

the end of this section).

The passive "fluoride plate" or "fluoride

candle" methods for monitoring ambient

fluorides have been used as a qualitative

index of gaseous fluoride levels (Korruri,

1984). These methods use a circular or

cylindrical filter paper impregnated with an

alkaline solution (Ontario Ministry of the

Environment, 1979; Bumbaco and Shelton,

1978, 1982). The "plates" or "candles" are

exposed to the atmosphere for a given time

period (of the order of a month) sheltered by

a petri dish or louvred case. Analysis

involves solution extraction of the filter paper

followed by analysis for total fluorides using

a fluoride ion-specific electrode. Resultant

fluoride concentrations are expressed as

fluoridation rates in units of μg F- cm-2 per 30

days. Identification and quantification of the

fluoride on the filter paper may also be made

using a mass spectrometer.

Table 4 Locations of coal-burning electricity generating utilities in Canada

Name Lat. (N) Long. (W) Name Lat. (N) Long. (W)

Glace Bay, N.S. 46.2 59.95 Richard L. Hearn, Ont. 43.7 79.33

Lingan, N.S. 46.2 60.03 Thunder Bay, Ont. 48.4 89.22

Maccan, N.S. 45.7 64.25 Brandon, Man. 49.8 99.88

Point Tupper, N.S. 45.6 61.37 Selkirk, Man. 50.2 96.87

Trenton, N.S. 45.6 63.63 Amy Street, Winnipeg, Man. 49.9 97.15

Chatham, N.B. 47.0 65.47 Boundary Dam, Sask. 49.1 102.98

Dalhousie #2, N.B. 48.1 66.40 Estevan, Sask. 49.1 102.98

Grand Lake #2, N.B. 46.1 66.02 Poplar River, Sask. 49.1 105.52

Atikokan, Ont. 48.8 91.62 Battle River, Alta. 52.6 112.07

J. Clarke Keith, Ont. 42.3 83.10 H. R. Milner, Alta. 53.9 118.50

Lakeview, Ont. 43.6 79.55 Sheerness, Alta. 51.5 111.67

Lambton, Ont. 42.8 82.43 Keephills, Alta. 53.5 114.55

Nanticoke, Ont. 43.6 79.55 Sundance, Alta. 53.5 114.55

Wabamun, Alta. 53.6 114.48

Source: Statistics Canada, 1990

Adams (1961) was able to derive an

equation which related data obtained from

limed papers to atmospheric HF levels. In

this work, HF was added to air entering a

growth chamber and, therefore, the only

fluoride present was HF. In addition to limed

papers, direct measurements of gaseous HF

were made (continuous air withdrawal,

fluoride adsorption onto a glass substrate,

followed by titration to measure fluoride)

which allowed the development of a

correlation between atmospheric HF and
Science Assessment Document for HF 13 CEPA/FPAC WGAQOG July 1996

fluorides trapped on the papers. This is a

very simple situation compared with field

measurement of ambient fluoride levels in

air. It was concluded that direct conversion

from limed paper data to atmospheric HF

concentrations in the field is not possible

(Adams, 1961), and that the limed papers

are only useful to delineate areas of fluoride

contamination, to determine relative

intensities of fluoride pollution among sites,

and to monitor changes in pollution intensity

due to reductions in emissions or addition of

new emission sources to an area. Sidhu

(1979) monitored atmospheric fluoride levels

in the vicinity of a phosphorous reduction

plant using both sodium formate papers

(which are also effective fluoride traps) and

sequential samplers. The use of these

different techniques at the same site allowed

the derivation of an equation that could be

used to calculate total atmospheric fluoride

concentrations (μg F- m

-3) from limed-paper

data (μg F- dm-2 week-1). However, since the

proportion of HF in the total atmospheric

fluoride load was not known, Sidhu (1979)

did not determine the amount HF in the

atmosphere at the monitoring sites. Adams

(1961) also acknowledged this shortcoming,

and pointed out that limed-paper monitoring

is susceptible to variation due to changes in

the environment, particularly to temperature

and wind velocity, both of which will affect

the amount of fluoride trapped by the

papers. Error rates of up to 50% have been

reported (Ontario Ministry of the

Environment, 1979; ASTM, 1991) since the

flux of fluoride to and from the collecting

surface (and its retention of it) depends

greatly upon local meteorological conditions.

However, passive methods are useful in

defining a potential area of environmental

impact from HF.

Double paper-tape samplers (dual-tape

samplers) have been developed for

monitoring ambient gaseous and particulate

fluorides (ASTM, 1991). Individual air

samples may be collected automatically over

time periods of minutes to three hours.

The paper tapes are removed from the

sampler and treated so as to dissolve the

fluoride, and the solubilized fluoride is

analyzed by potentiometric or photometric

methods. This monitoring method provides

the means of automatically separating and

collecting atmospheric particulate and acidic

gaseous-fluoride samples. Interferents with

the methodology are particulate-metal salts

and acid aerosols or gases which may

neutralize or acidify the alkali-treated tapes.

Contamination of the acidic gaseous-fluoride

fraction by small particulate fluorides (<1 μm)

is usual. For a one-hour sample, the

precision expressed as the relative standard

deviation is 5% in the range of 1 to 3 μg F

m

-3. Fluoride recovery is usually 95% for

known amounts of fluoride in the range of 2

to 20 μg m-3.

One review of double-tape sampling

methods has estimated detection limits of

0.07 μg HF m-3 for a 2-hour sample (Zankel

et al. 1987). However, operationally, large

variations in the measured ambient HF

concentrations monitored by dual-tape

samplers may occur due to variations in airsample flow rates (Bisson et al., 1995). Thus,

the accuracy of the method is questionable.

The precision of measurement of the trapped

HF is high; Bisson et al. (1995) have stated

that sample repeatability is satisfactory and

the percentage error small, with detection

limits of 0.3 μg F m-3 on the filter, and

quantification limits of 1.1 μg F m-3.

Nevertheless, until the sampling airflow

problems are solved, precise analytical
Science Assessment Document for HF 14 CEPA/FPAC WGAQOG July 1996

measurement of trapped fluoride is not

useful.

Commercial instruments, which use a liquid

scrubber and fluoride ion specific electrodes,

are available for continuous monitoring.

The measurement principle is to continuously

sample ambient air, removing solid particles

in a cyclone separator, and scrubbing the air

sample in an aerosol gas scrubber, followed

by analysis of the condensed aerosol gas

with the ion-selective electrode. Operational

detection limits are approximately

0.1 to 0.2 μg F m-3. There are no known

interferents with the methodology.

Real-time analysis of HF may also be

performed with an atmospheric pressure

chemical ionization tandem mass

spectrometer (De Brou et al., 1991). The ion

chemistry is dominated by dissociative

attachment reactions:

R

-

 + HX Ë X- + HR

where R refers to OH, SO2 or CO3 and X

refers to F- or Cl-. The X- ion may arise from

a variety of F- or Cl- containing species,

therefore this method is only a good identifier

of HF in the absence of other fluorinated

species. Established spectra are used to

identify HF in a complex matrix which

includes other fluorinated species. The

standard monitoring period is 30 minutes,

with instantaneous measurements acquired

every five seconds. Real-time detection limits

are in the range of 0.2 to 0.5 μg m-3.

3.4 ENVIRONMENTAL LEVELS IN

CANADA

Mean atmospheric levels in Canada range

from 0.01 to 1.0 μg F- m-3 (Environment

Canada, 1994). Current areas of concern in

Canada are in the provinces of British

Columbia, Ontario and Quebec. However,

future industrial installations with HF

emissions may warrant a study of ambient

HF levels elsewhere in Canada. No

information is available on indoor

concentrations.

The data in table 5 illustrate the variation in

HF concentration ranges across Canada.

More intensive and continuous monitoring

has been performed by the B.C. Ministry of

Environment, Lands and Parks in association

with Alcan in Kitimat, B.C., using a

continuous methodology, and by the Ontario

Ministry of Environment and Energy in

southern Ontario using fluoride candles.

Fig. 2 shows the variation in the monthly HF

concentration averages from January 1992

to July 1994 at each of four sites near

Kitimat. During that period, the average

monthly concentration exceeded the

recommended 30-day reference level of 0.4

μg m-3 twice at the Minnette site in 1992; for

five consecutive months (Jan. to May 1993)

at the Alcan Dock and once at the Workshop

site (July 1993).

HF monitoring by the Ontario Ministry of

Environment and Energy is performed to

establish relative amounts of gaseous

fluorides present over an extended

period of time, primarily to assess

vegetation effects (Ontario Ministry of

Environment and Energy, 1991, 1992). This

passive monitoring technique provides data

in units of μg per 100 cm2 per 30 days. This

information cannot accurately be translated

to μg m-3 (as discussed in previous section),

therefore the data presented in fig. 3 should

be viewed from the perspective of providing

information on relative changes in ambient

HF concentrations. There is no obvious

seasonal pattern over the two years. In 1991

and 1992, the highest annual arithmetic

means and monthly values were recorded
Science Assessment Document for HF 15 CEPA/FPAC WGAQOG July 1996

in Hamilton. This station is immediately

adjacent to a brick manufacturer.

3.5 AMBIENT AIR OBJECTIVES

AND STANDARDS IN OTHER

JURISDICTIONS

Various agencies around the world have air

quality objectives and guidelines for gaseous

fluorides (table 6). The United States has not

set a federal standard for gaseous fluorides

(as HF); however, the U.S., as required by

the U.S. Clean Air Act 1990, identified

potential hazards to public health and the

environment from HF considering a range of

events that included worst-case accidental

releases (Environmental Protection Agency,

1993). Analysis of public exposure to routine

emissions were not included due to the focus

on worst-case releases.

Additionally, other jurisdictions have

established a limit on vegetation fluoride

accumulation. These limits are also

summarized in table 6. Since they are based

on the same information as reviewed in this

document, it is not surprising that the limits

are essentially the same.

Table 5 Ambient HF concentration ranges at selected Canadian sites, 1980–91

Source and location Year(s) Dist.

(km)

Statistic Concentration

range (μg m

-3)

Reference

1. Lead and zinc mining

and phosphate fertilizer

operation, Trail, B.C.

1990–91 <5 mean levels 0.43–0.59 EC†, 1993

2. Lead and zinc smelter

and fertilizer operation,

Trail, B.C.

1984–85 0.6–10.5 range 0.13–0.60 White et al.,

1986

3. Hydrofluoric acid plant,

Amherstburg, Ont.

1987–90 near growing

season

0.076–2.36 Gizyn, 1991

4. Steel plant,

Hamilton, Ont.

1991 near mean 0.17–0.24 EC, 1993

5. Residential area,

Toronto, Ont.

1981 mean 0.03 McGrath,

1983

6. Brick manufacturing

plant, Brampton, Ont.

1980–81 0.8 mean 0.07–0.73 McGrath,

1983

7. New York Aluminum

smelter, Cornwall

Island, Ont.

1987–91 1.6–4 mean 0.43–0.85 EC, 1994

8. Aluminum smelters,

Quebec

8 mean 0.1–0.71 EC, 1993

9. Lead smelter,

Belledune, N.B.

1988–90 near yearly avg. 0.027–0.06 Murphy,

1991

10. Phosphorous reduction

plant, Long Harbour,

Nfld.

1980 1.4

8

18.7

average 2.45

0.4

0.06

EC, 1994

11. Background, Alert,

N.W.T.

remote mean 0.00568 Barrie and

Hoff, 1985
Science Assessment Document for HF 16 CEPA/FPAC WGAQOG July 1996

Source: Environment Canada, 1994

† EC = Environment Canada
Science Assessment Document for HF 17 CEPA/FPAC WGAQOG July 1996

Fig. 2 Average monthly ambient HF concentration from January 1992 through July 1994

at four sites near Kitimat, B.C..
Science Assessment Document for HF 18 CEPA/FPAC WGAQOG July 1996

Fig. 3 HF fluoridation rate monthly averages for Ontario, 1991–92, for: (a) urban areas

and (b) rural areas.

(a) 

(b) 
Science Assessment Document for HF 19 CEPA/FPAC WGAQOG July 1996

Table 6 Ambient air quality standards and objectives for gaseous fluorides (μg m-3), and

fluoride levels in vegetation (μg g-1 DW), in other jurisdictions

Jurisdiction 90 days 30 days 7 days 24 hours 12 hours Other Vegetation

content

Canada (proposed

Reference Levels)

0.4 0.4 0.5 1.1 — — 30

Manitoba —

—

—

—

—

—

0.40 D†

0.85 A

—

—

—

—

—

—

Newfoundland — 0.45 — 0.90 — — —

Ontario (Apr. 15 to

Oct. 15)

— 0.34 — 0.86 — — —

British Columbia — 0.35 0.55 0.85 — — —

Montreal Urban

Community

— 0.34 — 0.86 — 1.85

(8 hours)

2.00

(1 hour)

—

Kentucky — 0.82 1.64 2.86 3.68 — gr. season -

40

2-mo. - 60

1-mo. - 80

Maryland — — — 1.20 — 0.4 (72

hours)

—

New York — 0.80 1.65 2.85 3.70 — —

South Carolina — 0.80 1.60 2.90 3.70 — —

Tennessee — 1.20 1.60 2.90 3.70 — —

Washington — 0.84 1.70 2.90 3.70 0.5 (Mar. to

Oct.)

—

Australia

New South Wales — 0.84 1.7 2.9 3.7 — —

Victoria 0.59 — 2.0 2.9 — — —

Japan — — 0.5 1.0 — — —

Netherlands — 0.8 — 2.8 — 0.4

(growing

season)

—

New Zealand — 0.5 1.0 — — 70 (1 hour)

Norway — 0.4 — 1.0 — — —

Sources: (Streeton, 1990; International Union of Air Pollution Associations, 1992

† D = desirable; A = acceptable
Science Assessment Document for HF 20 CEPA/FPAC WGAQOG July 1996

4 EFFECTS ON VEGETATION

A considerable amount of research has been

conducted on the effects of fluoride on

higher plants, with a number of extensive

review articles written. This section is based

primarily on a review of the following

references: Drury et al. (1980), Environment

Canada (1994), Linzon (1971), McLaughlin

(1991), Miller (1993), National Research

Council (1971), Thomas and Alther (1966),

Treshow and Pack (1970), Weinstein (1970,

1977) and Zwiazek (1994).

4.1 EFFECTS OF FLUORIDES ON

VEGETATION

Injury to plants results from absorption of

fluoride by the plant. Gaseous fluorides are

readily absorbed, whereas particulate

fluorides collect on external surfaces and

cause little or no injury unless dissolved by

precipitation or dew and absorbed.

Absorption of atmospheric fluorides by plants

can result in high concentrations of fluoride

in leaves, but only slightly elevated amounts

have been found in stems and roots. Injured

portions of leaves usually contain more

fluoride than uninjured portions. The lowest

concentrations of fluoride are found in the

fruit and seeds of plants. The length of plant

exposure to atmospheric fluoride is important

because the effect of fluoride is cumulative.

However, inactivation of fluoride within the

plant, growth dilution, physiological condition

of the plant, plant nutrient status, fumigation

dynamics, stomatal activity and loss from the

plant make direct comparison between

concentrations of fluoride in the air and plant

impossible.

While a considerable amount of work has

been carried out on non-visible or metabolic

fluoride injury, the exact mechanisms by

which fluorides injure higher plants are not

well known. Much of this work has involved

the study of various enzymes, systems or

organelles in vitro by exposing whole plants

or plant parts to sodium fluoride solutions.

Fluorides have been found to inhibit or

stimulate enzymes involved in glycolysis,

respiration, photosynthesis, metabolite

transport across membranes and other

processes. Depending on many factors,

fluorides may inhibit or stimulate respiration,

which is one of the earliest symptoms of

fluoride toxicity. Respiration inhibition is

possibly linked to the inhibition of respiratory

enzymes, while stimulations may be linked to

fluoride acting as an uncoupler of

phosphorylation. In vitro, fluorides may affect

membranes by inhibiting ATPase, disrupting

the membrane pH gradient, and blocking

chloride antiport movement. In vivo

experiments involving HF fumigation of white

pine seedlings show that changes in

membrane permeability, greater electrolyte

leakage, plasma membrane lipid composition

and increased plasma membrane ATPase

activity occur during the early stages of

fluoride injury. No changes in mesophyll cell

structure were observed before the

appearance of visible injury.

The mechanisms by which some plants are

more tolerant to fluoride than other plants

are also not well understood. Tolerant plants

may be able to deactivate fluoride better

than sensitive plants. Possible mechanisms

of fluoride deactivation in plants include

shifts to fluoride insensitive metabolic

pathways, removal from sites of enzyme

inhibition via reactions with organic

compounds, reaction with cationic sites,
Science Assessment Document for HF 21 CEPA/FPAC WGAQOG July 1996

sequestration in vacuoles, and translocation

to the leaf surface. In addition to

physiological effects, fluorides can cause

mutagenic effects such as chromosomal

aberrations, bridges, fragments and

multipolar mitosis.

A number of factors influence the action of

fluorides on vegetation and the uptake and

accumulation of fluoride by plants. These

factors include temperature, relative

humidity, wind speed, soil moisture, plant

nutrition, stage of growth and plant species.

Injury symptoms similar to those caused by

atmospheric fluorides may also be due to

other agents, such as insects, disease,

nutritional disorder, and adverse weather.

Gaseous fluorides enter the leaves of plants

primarily through the stomata. Injury rarely

occurs at the absorption site, as the fluorides

dissolve within the aqueous phase of the

substomal cavity and move as ions through

the apoplastic space of the mesophyll cell

walls with the transpirational stream to the

leaf tips and margins, where fluoride

accumulates. When the accumulated fluoride

concentration exceeds a certain threshold

level, which varies with plant species and

with varieties of the same species, leaf injury

occurs. Fluoride injury symptoms vary

considerably, depending on whether the

vegetation is narrow-leaved or broad-leaved,

relative susceptibility to fluoride, the

concentration in the air, and duration of

exposure. The injury may take the form of

chlorosis (yellowing of the leaves due to

chlorophyll reduction) or necrosis (killing of

leaf cells). In general, plants injured by

chronic atmospheric fluoride usually display

leaf chlorosis. Necrosis generally occurs at

the leaf tips and margins, and these necrotic

areas may be separated from healthy leaf

tissue by a darker zonate line. All forms of

injury are not present in all injured plants.

Fluoride injury to plants may be acute or

chronic. Acute fluoride injury is caused by

short-term exposures to high concentrations

of atmospheric fluorides. Inactivation and

translocation of fluoride cannot keep pace

with absorption, resulting in leaf lesions. The

amount of accumulated fluoride could be

less than that required to cause chronic

injury because sudden absorption of high

concentrations of fluoride disrupts plant

metabolism quickly. Chronic fluoride injury is

caused by variable exposure periods at

different concentrations of atmospheric

fluoride. Plants absorb fluoride slowly and

the unidirectional distal movement of the

fluoride eventually results in the

accumulation of concentrations sufficient to

cause injury or cell death. The concentration

of fluoride in the leaf tips and margins or

injured areas is higher than in the rest of the

leaf. Lesions continue to enlarge as the

plants are subjected to low concentrations of

atmospheric fluorides. With continued

exposure, the necrotic areas spread inward

from the margins of leaves of dicotyledonous

plants and downward from the leaf tips of

conifers and monocotyledonous plants. The

necrotic areas may extend across large veins

and even cross the midrib in deciduous

leaves. (This is a pattern seldom seen in

sulphur dioxide-caused lesions.) Premature

defoliation follows leaf injury on some plants,

and while others retain their leaves, the

leaves often have desiccated margins that

break away. Exposure of coniferous tree

foliage to atmospheric fluoride results in

chlorotic needle tips followed by reddening

(likely needle necrosis). Needle elongation is

retarded and the needles may be shed

prematurely. Corn leaves, if not actually

injured with collapse of leaf areas, show a
Science Assessment Document for HF 22 CEPA/FPAC WGAQOG July 1996

general mottled appearance. In Gladiolus, tip

burn gradually extends down the leaf and

kills all tissue, including veins. As the fluoride

concentration increases and duration

decreases, marginal injury predominates,

expanding across the leaf, occasionally

leaving an isolated green tip. In rare

instances, flower bracts might develop

marginal burn in a severe fumigation, with

the petals sometimes displaying injury. Some

investigators have observed a black tip

condition in cherries, while others have noted

a soft spot along the suture line of peaches

following HF exposure. Fruit drop and poor

fruit set have been observed in orchards

subjected to heavy fumigations.

4.2 FLUORIDE ACCUMULATION IN

VEGETATION

In Ontario, maple foliage ranges from >0.5

to 10 μg F g-1 DW. Plants exhibit a broad

range in their sensitivity to injury from

atmospheric fluorides. Sensitivity varies not

only among species but among varieties of

the same species. Sensitive plant species

include varieties of apricot, barley, blueberry,

sweet corn, Douglas fir, Gladiolus, grape,

Manitoba maple (box elder), peach, pine,

plum, St. John's wort, tulip, and western

larch. Sensitive varieties of Gladiolus and

strains of eastern white pine may display leaf

injury with accumulations of less than

30 μg g-1 DW in the injured leaves. Plants of

intermediate resistance, such as apple and

raspberry, may not display injury until they

have accumulated 100 μg g-1 DW. Plants

strongly resistant to fluorides, such as wheat

and alfalfa, may not display leaf injury until

accumulated concentrations exceed

200 μg g-1 DW. Bitternut hickory can

accumulate up to 1,000 μg g-1 DW and

display no foliar injury. The relative sensitivity

of different plant species and varieties to

fluoride is generally based on visible foliar

injury symptoms and their relationship to

fluoride dose, fluoride concentration in the

leaf, or threshold dose for visible foliar injury.

However, it has recently been shown

(McLaughlin, 1991) that for nine tree species

there was very little agreement between the

fluoride sensitivity ratings based on foliar

injury and sensitivity ratings based on the

reduction of annual xylem growth during a

20-year period of high fluoride emissions

around an aluminum smelter. Oak and

maple, which were classed as tolerant based

on foliar injury, were sensitive to intermediate

based on xylem growth.

Accurate prediction of fluoride accumulation,

and knowledge of plant responses to

accumulated fluoride, would allow the

establishment of guidelines which would limit

fluoride uptake and minimize

fluoride-induced damage. In its most simple

form, uptake can be expressed as

Fv = kCt + b [1]

where Fv is plant fluoride content

(μg F g-1 DW), k is the accumulation

constant for the species, C is the ambient

concentration of HF (μg m-3), t is the duration

of exposure (days), and b is the y-intercept

(theoretically, b is the amount of fluoride

present in the tissue as a result of

accumulation from natural sources). Gritsan

(1992) developed predictive equations based

on the format of equation [1] for field-grown

wheat and barley, and for seedlings of wheat

and barley grown in growth chambers.

Accumulation constants for barley were

two-fold greater than for wheat in both

environments. Accumulation of fluoride has

been examined in grapevine (Doley, 1982),

where it was found that both b and k varied
Science Assessment Document for HF 23 CEPA/FPAC WGAQOG July 1996

with the total dose provided to the plants.

MacLean and Schneider (1973) compared

fluoride accumulations in continuously

fumigated forage (a mixture of timothy grass

and red clover) to fluoride accumulations in

plants intermittently fumigated with HF.

Plants exposed continuously to HF

accumulated more fluoride than those

exposed intermittently to the same total HF

dose. Investigations of fluoride accumulation

by orchard grass and alfalfa led McCune and

Hitchcock (1971) to derive predictive

equations based on the format of equation

[1]. However, while these regressions were

highly significant, they only accounted for

54% (orchard grass) and 70% (alfalfa) of the

variability. Further investigation revealed that

the time between the end of the exposure

period and sampling was an important

parameter in determining fluoride levels. In

alfalfa, fluoride concentrations declined with

an apparent half-life of about eight days. To

account for this, the regression equation

Fv = 4.21C 0.82 t 0.70 e -0.032D [2]

was derived, where D is the number of days

between the end of fumigation and the time

that the samples were harvested for

analysis, and e is the base of the natural

logarithm. Similar analysis of the

post-fumigation period length only slightly

improved the regression fit for orchard grass,

and this improvement was not statistically

significant.

Some plants are able to reduce leaf internal

fluoride levels by exporting fluoride to the

exterior leaf surface. This ability varies by

species, with cotton and tomato being

relatively efficient at exuding fluorides

(Jacobson et al., 1966). Davison (1982)

reviewed the literature on the loss of fluoride

from leaves, and noted that losses may be of

the same magnitude as accumulation rates.

In a very simplistic sense, foliar fluoride may

be considered to be compartmentalized into

interior and exterior compartments. Fluoride

which remains in the interior compartment

may be physiologically active, while that on

the exterior is not. Under natural conditions,

rainfall may wash the leaves of exterior

fluorides. De Temmerman (cited in van der

Eerden, 1991) accounted for the effect of

rainfall and the decline in fluorides as a

function of time with the equation

Fv = 128F3

0.13 F20.59 F10.45 e-0.0043N [3]

where F1, F2 and F3 are the average

ambient fluoride levels in the preceding

1st, 2nd and 3rd weeks prior to grass

sampling, respectively, and N is the rainfall

(mm) in the preceding two weeks. Variation

in the amount of foliar fluoride with the

season was observed by van der Eerden

(1991), who incorporated a "seasons index"

into his predictive model.

As illustrated by these equations, the

accumulation of fluoride by plants is

dependent upon the amount of fluoride, the

pattern of fluoride exposure, the plant

species, and the environment before, during

and following exposure. These models

generate valid predictions only under the

conditions from which the data originate (van

der Eerden, 1991; MacLean et al., 1989).

The reverse of this situation (i.e., the use of

vegetation fluoride content as a quantitative

measurement of ambient HF levels) is also

invalid (MacLean et al., 1969), although

vegetation fluoride monitoring can be used

as a qualitative tool to assist in the diagnosis

of injury and in the identification of fluoride

sources. Chemical analysis is a valuable tool

in diagnosing fluoride injury. Plants in

polluted areas continually accumulate

fluoride, and thus repeated analysis can

indicate the relative intensity of injury. Also,
Science Assessment Document for HF 24 CEPA/FPAC WGAQOG July 1996

the fluoride emission source can usually be

determined since the fluoride concentration

in plants increases with proximity to the

source.

When considering fluoride content of plants

to be used as forage, all forms of fluoride

must be taken into account since all fluorides

are metabolically active (to differing degrees)

within a herbivore. To account for both

gaseous and particulate loadings onto

forage (grass), Blakemore (cited in van der

Eerden, 1991) derived the regression

Fv = -31.1 + 0.67FG1 + 281FAg + 223FAp [4]

where FG1 is the fluoride content of the grass

one week prior to sampling, and FAg and FAp

are the average atmospheric gaseous and

particulate fluoride concentrations during the

preceding week, respectively. Consideration

of both particulate and gaseous fluorides is

necessary in areas close to facilities which

emit fluorides, since both forms are likely to

be present in and on the plant.

Analysis of washed tissues will provide an

indication of the internal fluoride content of

the tissue. The analysis of unwashed tissue

samples will result in a determination of total

fluoride content, which includes internal and

external fluorides. When analyzing for

fluoride levels in forage, determination of

total fluoride is the only meaningful, practical

analysis. For the protection of livestock and

wildlife, limits on forage fluoride content have

been proposed or established. A limit of

55 μg F g-1 DW has been suggested by

van der Eerden (1991). Kentucky standards

include limits of 80, 60 and 40 μg F- g-1 DW

in forage for average 1-month, 2-month

and growing season fluoride levels,

respectively. These limits were proposed by

Suttie (1969), and were accepted by Mitchell

et al. (1981) and adopted by the State of

Kentucky (table 6). A maximum of 20 to

30 μg F g-1 DW is suggested for forage

fluoride content in section 5 of this

document. The ambient guidelines proposed

for HF will probably not result in the

accumulation of fluorides in amounts which

would induce fluorosis. However, near

sources of fluoride emission where plants

are exposed to multiple forms of fluoride,

monitoring of fluoride content in unwashed

forage samples is necessary to ensure that

animals are not exposed to harmful dietary

fluoride levels.

Soil normally contains between 20 and 500

ppm fluoride. In Ontario, the typical range for

fluoride in medium to fine textured soils is

between 20 and 160 ppm. Atmospheric

fluoride emissions that are not removed by

other receptors eventually settle on soil and

increase its fluoride content. The application

of fertilizer can also increase soil fluoride

content. In alkaline soils, most of the fluoride

is immobilized on clay particles with little root

uptake occurring in plants. More fluoride is

soluble in acidic or saline soils, where

sodium replaces calcium as the dominant

cation, and greater root uptake takes place.

The lesions on leaves caused by uptake of

soluble fluorides from soils are quite similar

to those caused by absorption of

atmospheric fluorides, but in some species

there tends to be a greater degree of injury

to the interior than to the margins of leaves.

Analyses show that plant roots can contain

very high fluoride concentrations (1,000 to

6,000 μg g-1 DW) when fluoride enters from

the soil, whereas the concentration is very

low (about 10 μg g-1 DW) in roots when

fluoride enters via the leaves.

There has been little research conducted on

the effects of accumulated fluorides on

insects. Jia-xi and Yong-mei (1988) found a
Science Assessment Document for HF 25 CEPA/FPAC WGAQOG July 1996

threshold level of about 30 μg F- g-1 DW in

mulberry leaves for an effect of fluoride on

feeding silkworms (increased mortality,

decreased weight gain in larvae). Insects

(pollinators, predators, foliage feeders, and

cambial region feeders) collected from an

area near a fluoride emission source were

found to have elevated fluoride levels

relative to those collected from control areas

at least 50 miles distant from the source

(Dewey, 1973). Pollinating and foliage

feeding insects accumulated the most

fluoride. The effects of the accumulated

fluoride on insect physiology, reproduction,

and behaviour were not investigated.

4.3 CANADIAN CASE STUDIES

Common industrial sources of fluoride

emissions in Canada include the production

of super-phosphate fertilizers, uranium

hexafluoride, hydrofluoric acid,

chlorofluorocarbons, fibreglass, appliances,

ceramic tiles, bricks, aluminum smelting and

casting, steel manufacturing, and

petrochemical refineries. Listed below are a

number of examples documenting the impact

of fluoride emissions on vegetation in the

vicinity of some these industrial sources.

The range of impact from a given source is

usually estimated from observed fluoride ion

concentrations in vegetation and surface

materials such as leaf litter or snow. For the

Long Harbour, Newfoundland, phosphorous

reduction plant (no longer in operation) over

a 20-week period, no vegetation damage

was observed beyond 13 km from the source

(Sidhu, 1979). Extrapolating from leaf litter,

rain and snow water fluoride measurements,

the range of impact did not extend beyond

30–35 km from the source (Sidhu, 1982a,

1982b). Comparison of snow fluoride

concentrations near two aluminum smelters

within the Saguenay–Lac Saint-Jean region

of Quebec before 1978 and after the 1984

completion of a depollution program showed

that the area of influence (defined as total

fluoride levels >50 μg L-1 melted snow) was

approximately 3,000 km2 and 100 km2,

respectively (Ouellet, 1987). It was further

surmised that the greater portion of this

reduction was attributable to reductions in

particulate fluorides rather than to gaseous

HF. It was estimated that in 1975, HF

represented 50% of the volatilized fluoride

emissions from the aluminum smelters, and

approximately 80% in 1984. It is not

expected that the impact from HF emissions

would extend beyond approximately 30 km

from a given major source.

4.3.1 Phosphorus Reduction

Long Harbour, Newfoundland

A number of major studies on the various

effects of fluoride emissions on vegetation

have been conducted in the vicinity of a

phosphorus reduction plant at Long Harbour,

Newfoundland (Linzon, 1978a; Roberts and

Thompson, 1980; Sidhu 1979, 1982a,

1982b; Sidhu and Staniforth, 1986;

Staniforth and Sidhu, 1984; Thompson et al.,

1979). The facility first became operational in

1968 and fluoride injury to trees was first

observed in 1970. Fluoride emissions were

both gaseous and particulate, with the

impact of the particulate being restricted to

the immediate vicinity of the plant. HF and

SiF4 are the main fluorides emitted. The

investigation of the fluoride impact was

conducted to a distance of 20 km downwind

of the facility in 1973, 1974 and 1975

(Thompson et al., 1979). Injury to balsam fir,

black spruce and white spruce ranged from

complete defoliation to trace tip burn.
Science Assessment Document for HF 26 CEPA/FPAC WGAQOG July 1996

Marginal fluoride injury was observed on

white birch and alder. Fluoride levels in

conifer foliage ranged from 281 μg g-1 DW in

the severely injured zone to 44 μg g-1 DW in

the lightly injured zone to 7 μg g-1 DW in

controls. Soil fluoride concentrations ranged

from 908 ppm to 58 ppm to 10 ppm in the

respective zones. Fluoride deposition to the

soil was five times greater from precipitation

than from leaf litter (Sidhu, 1982a, 1982b).

In black spruce needles, fluoride levels of

100 to 200 μg g-1 DW covered 12 km2, 50 to

100 μg g-1 DW covered 31 km2, 20 to

50 μg g-1 DW covered 23 km2, and 10 to

20 μg g-1 DW covered 88 km2. The extent of

observed fluoride injury covered 80 km2; no

visible injury was observed with foliage levels

up to 20 μg g-1 DW.

In 1976, foliage of balsam fir, black spruce,

larch and white birch displayed severe

symptoms of fluoride injury up to a distance

of 8 km from the source. Moderate

symptoms were observed between 8 and 9

km, light symptoms from 9 to 12 km, and no

symptoms beyond 12 km (Sidhu, 1979).

At the end of the 1976 growing season,

maximum fluoride concentrations in the

foliage of these tree species in the zone

between 0 and 12 km from the plant were

265, 96, 411, and 357 μg g-1 DW,

respectively. Beyond 12 km, the fluoride

concentrations in the foliage of the same

tree species were less than 20 μg g-1 DW.

Air monitoring, using sodium-formate plates,

gave a calculated maximum fluoride level of

about 5 μg m-3 (6.1 ppb) at a distance of

0.7 km from the source. Beyond 12 km, the

calculated level was 0.20 μg m-3 (0.24 ppb)

or less.

During another investigation of forest

damage at Long Harbour in the summer of

1977, it was observed that over 80% of the

dominant balsam fir and black spruce trees

within 5 km north of the phosphorus

manufacturing plant had been killed (Linzon,

1978a). Chemical analyses of samples

collected from balsam firs showed fluoride

foliage levels over 100 times higher at a

distance of 2 km from the source than at

20 km. Considerable amounts of fluoride

could be washed off the affected foliage,

suggesting that both particulate and gaseous

fluorides were present in the area’s fluoride

emissions.

Fluoride levels in the lichens Cladina

raniferina and Cladina stellaris correlated

inversely with distance from the phosphorus

reduction plant at Long Harbour, following

the direction of the prevailing NE winds

(Roberts and Thompson, 1980). Fluoride

concentrations in the lichens ranged from

2,830 μg g-1 DW in the severely damaged

area to 15.5 μg g-1 DW in the lightly

damaged area to 6.4 μg g-1 DW in controls.

Trace damage occurred at concentrations of

25 μg g-1 DW. Symptoms consisted of

discolouration and loss of structure. The

fluoride concentration in lichens was twice

that of the soil humus and half that of

bryophytes at the sample locations.

The effects of fluoride emissions on the

flowering and fruit production of blueberries

and raspberries, and on the foliage, cones

and seeds of balsam fir, black spruce and

larch were studied at six sites downwind from

the Long Harbour plant in the summer of

1982 (Sidhu and Staniforth, 1986; Staniforth

and Sidhu, 1984). Fluoride levels, using

sodium-formate plates, ranged from

11.38 μg F m-3 at 1.4 km to 0.08 μg F m-3

at 18 km. The highest levels occurred in July

during the flowering of the blueberries and

raspberries. Flower mortalities were 89% for

blueberries and 78% for raspberries at the
Science Assessment Document for HF 27 CEPA/FPAC WGAQOG July 1996

highest fluoride site with a 21- and 10-fold

reduction in seed production respectively, as

well as a significant decrease in size,

quantity and dry weight. Fluoride levels in the

foliage ranged from 403 and 216 μg g-1 DW

to 8 and 9 μg g-1 DW for raspberry and

blueberry, respectively. Fluoride injury was

observed on the raspberry foliage. At the

same six locations, chlorosis, necrosis,

needle damage and defoliation to balsam fir,

black spruce and larch occurred when the

fluoride concentration of the foliage

exceeded 20 μg g-1 DW. Injury occurred

where airborne fluoride levels exceeded

0.85 μg F m-3. Reduction in seed size,

germination rate, number of seeds per cone,

number of cones per tree, number of fertile

trees, and size reduction, distortion, or

mortality of cones occurred under the same

fluoride gradient as for the blueberry and

raspberry. Seed production on the windward

side of the trees was significantly less than

on the leeward side. Reproduction failure

and past mortality of fluoride damaged

conifers have resulted in their being replaced

by the more tolerant hardwoods, birch and

alder. It is important to note that the

calculation of airborne fluoride levels (in μg F

m

-3) from the sodium-formate plate data is

specific for only this study, and represents

total fluoride levels, rather than gaseous HF

levels.

4.3.2 Phosphorus Fertilizer Production

Port Maitland, Ontario

Inorganic fluoride emissions from a

phosphorous fertilizer facility in Port

Maitland, Ontario, was associated with

damage to conifers and deciduous trees

facing the prevailing winds (Hall et al., 1968).

The Ontario Ministry of the Environment

conducted extensive terrestrial assessment

surveys around the facility from 1969 until

1985, one year after it ceased manufacturing

operations in July 1984 (McLaughlin, 1981,

1986). Forage was collected biweekly during

the growing season from 1975 to 1980 as

part of a control order that would result in

the temporary shutdown of the facility if the

average fluoride content of the foliage

exceeded 80 ppm (80 μg g-1 DW, unwashed

material) for any one-month period,

60 μg g-1 DW for any two-month period, or

35 μg g-1 DW over the growing season. After

1980, collections were made on a one-month

basis. In 1984, at a location 2,300 m east of

the plant fluoride levels ranged from

17 ppm μg g-1 DW in April to 40 μg g-1 DW

in August and back down to 11 μg g-1 DW

in October. Similar levels and seasonal

pattern had been observed at the same

location in 1979 and 1980. During the

same period, 4,600 m east of the plant,

fluoride levels in foliage ranged from 2 to

5 μg g-1 DW and there was no seasonal

pattern. In 1985, fluoride levels in foliage

dropped to 7 to 14 μg g-1 DW at the first

location and <1 to 2 μg g-1 DW at the second

location, with no seasonal trend observed.

The pattern of fluoride levels in forage near

the gypsum setting ponds over a seven year

period, as old ponds were capped and new

ponds brought on line, showed that these

ponds were a significant localized source of

fluoride emissions.

Fluoride levels (unwashed) and injury

evaluations of maple foliage (red, silver,

sugar and Manitoba) were determined at

30 locations within 6 km of the plant in

September of each year. The highest

fluoride level in 1984 was 67 μg g-1 DW, 500

m east of the plant and 26 μg g-1 DW, 600 m

south of the plant. Both stations had levels of

400 μg g-1 DW in 1982 and 1983, and

840 μg g-1 DW and 1,270 μg g-1 DW,
Science Assessment Document for HF 28 CEPA/FPAC WGAQOG July 1996

respectively, in 1979. There was a steady

increase in the fluoride levels of maple

foliage throughout the growing season.

In 1979, 500 m east of the facility, fluoride

levels were 50 μg g-1 DW in June,

255 μg g-1 DW in July and 840 μg g-1 DW in

September. Injury on maple foliage in 1983

was observed up to 3.2 km NE of the facility.

In 1984, it was limited to two sites within

500 m, and there was no injury in 1985.

Wild grape, a fluoride-sensitive species, was

used to delineate the zone of fluoride injury

around the operation. In 1983, the injury

zone extended 5 km NE of the plant and

covered an area of 23.6 km2. This zone

remained unchanged (24.2 km2) in 1984 and

decreased to 1.4 km2 in 1985.

4.3.3 Aluminum Reduction

Cornwall Island, Ontario

Studies were started in 1969 on Cornwall

Island, Ontario, to document the effects of

fluorides emitted from an aluminum reduction

plant located immediately to the south, in

Massena, New York (Linzon, 1971). At a

sampling station about 1.6 km NE of the

plant, eastern white pine needles had

accumulated 135 μg g-1 DW fluoride. The

pines displayed an orange-red terminal

necrosis on their needles, showing severe

injury; many were dead. Trembling aspen

trees had 495 μg g-1 DW fluoride in injured

foliage and displayed reddish-brown

marginal lesions. At a control location about

6.4 km NE of the source, eastern white pine

and trembling aspen foliage displayed no

injury and contained less than 20 μg g-1 DW.

Since 1959, the aluminum company had

emitted 139 kg F hr-1 until abatement

measures in 1972 reduced the emissions to

about 34 kg F hr-1. The eastern white pines

on Cornwall Island demonstrated a

remarkable recovery in the radial growth

following the abatement measures

(McLaughlin and Emerson, 1984), and little

or no fluoride injury has occurred on the new

growth of needles (Linzon, 1986). The levels

of fluoride in maple foliage and injury to

sensitive species has remained relatively

constant since 1978 (Emerson, 1994b). In

1993, the highest level of fluoride in

unwashed maple foliage was 155 μg g-1 DW

at the site 1.6 km NE of the facility, and

fluoride levels decreased rapidly with

increasing distance.

A dendroecological study was conducted on

nine tree species found on Cornwall Island in

order to determine sensitivity ranking based

on annual tree ring-growth reduction and to

determine if reduction in growth occurred in

the absence of foliar injury (McLaughlin,

1991). The study looked at growth over three

periods: pre-operation of the aluminum

smelter, 20 years of high, uncontrolled

fluoride emissions and 12 years of reduced

fluoride emissions. All species except green

ash showed significant growth reductions

during the period of high emissions. There

was no growth reduction during the period of

reduced emissions. During the period of high

emissions, there was a deterioration in the

relationship between climate and growth,

and a consistent relationship between

reduced growth and fluoride levels in

vegetation and air. Based on growth

reduction, the ranking of the nine species

from most sensitive to least sensitive was:

trembling aspen, sugar maple, eastern white

pine, red oak, American beech, basswood,

shagbark hickory, black cherry, and ash.

Based on growth reduction, trembling aspen,

red oak and sugar maple were more

sensitive than the literature rankings based

on foliar injury, while black cherry was more

tolerant. The study concluded that foliar
Science Assessment Document for HF 29 CEPA/FPAC WGAQOG July 1996

injury is an unreliable indicator of the total

effect of fluoride on forest trees.

4.3.4 Aluminum Reduction

Arvida, Quebec

Studies were conducted on the effects of HF

on epiphytic lichens and mosses near an

aluminum reduction facility at Arvida,

Quebec (Leblanc et al., 1971, 1972). Lichen

and moss-bearing bark discs were cut from

trees in an unpolluted area, fixed to trees at

various sites near the aluminum facility, and

left for periods of 4 and 12 months. At a

distance of 1 km from the source, the lichens

accumulated 990 μg g-1 DW fluoride in 4

months compared to 70 μg g-1 DW in a

control area located 40 km from the source.

During the same period, mosses

accumulated 570 μg g-1 DW fluoride in

compared to 20 μg g-1 DW in the control

area. Both species accumulated fluorides

even at a distance of 15 km from the

aluminum plant (190 μg g-1 DW in lichens

after 4 months, and 78 μg g-1 DW in mosses

after 12 months). They also calculated an

index of atmospheric purity (IAP) which was

based on the number of epiphytes,

frequency of coverage and the resistance

factor of each epiphyte found on Populus

balsamifera at 42 sites covering an area of

250 km2 within 15 km of the facility. While a

total of 54 epiphytes, 9 bryophytes and 45

lichens were recorded within the study area,

none was found within one kilometre of the

facility. IAP values ranged from 0, indicating

no epiphytes found, near the plant to 103

away from the facility. The IAP values

increased with increasing distance from the

facility, suggesting that fluoride emissions

from the facility were affecting both the

density and frequency of epiphytes on

Populus balsamifera.

4.3.5 Aluminum Manufacturing

Kitimat, British Columbia

A study of the effects of atmospheric

fluorides on tree growth in the vicinity of an

aluminum manufacturer at Kitimat, British

Columbia, was started in 1973 (Bunce, 1984,

1985). A grid pattern containing 64

permanent sample plots was established,

increment cores were taken from the trees to

measure tree growth, and foliage was

collected for chemical analysis of fluoride

content. The forest area surrounding the

smelter was segregated into an inner zone

(high effect), an outer zone (low effect), and

a surrounding zone (no effect). Hemlock

forests were severely damaged in the inner

zone to a distance of about 8 km from the

smelter. The growth rate of the forests from

1954 to 1973 was reduced by 28% in the

inner zone and by 19% in the outer zone

compared to growth rates before the smelter

began operation in 1954. Fluoride in hemlock

foliage in 1974 measured 271 μg g-1 DW in

the inner zone, and 163 μg g-1 DW in the

outer zone. Abatement measures were taken

at the smelter in 1974, and from 1974 to

1979, the rate of fluoride emission was

reduced by 64% of pre-1974 emissions (from

5,500 kg day-1 to 2,000 kg day-1). The tree

growth reduction of 2,800 m3 per year

declined to 620 m3 during 1974–79. The

fluoride content of hemlock foliage in the

inner zone decreased to 87 μg g-1 DW in

1979, and to 29 μg g-1 DW in the outer zone.

The basal area decrease in forest growth

remained high in the inner zone for the

period 1974–79, but a small positive

increase in forest growth occurred in the

outer zone.
Science Assessment Document for HF 30 CEPA/FPAC WGAQOG July 1996

4.3.6 Aluminum Engine Casting

Windsor, Ontario

Fluoride accumulation in silver maple foliage

and grass was found around a large

aluminum engine casting plant in Windsor,

Ontario (Gizyn, 1994). Fluoride injury was

limited to trace amounts on wild grape within

400 m of the plant. Fluoride levels in

unwashed grass ranged from 183 μg g-1 DW

100 m east of the plant, to 2 μg g-1 DW 1 km

west of the plant. Fluoride levels in

unwashed silver maple foliage ranged from

188 to 20 μg g-1 DW. The pattern of elevated

fluoride levels in grass and maple was

correlated with the prevailing wind patterns.

4.3.7 Uranium Processing

Port Hope, Ontario

Since 1974, the Ontario Ministry of

Environment and Energy has conducted

annual assessment surveys to monitor the

impact of emissions from a uranium

processing plant on the local terrestrial

ecosystem (McLaughlin, 1988). The facility in

Port Hope, Ontario, produces uranium

hexafluoride and uranium dioxide; fluoride

and uranium are emitted into the atmosphere

during production. In 1986, trace to light

injury (<1% to 10% injury to individual

leaves) was observed on Manitoba and silver

maple (moderately sensitive to fluoride)

within distances of 300 to 750 m. In 1987,

the same zone was rated at moderate (11–

35%) to severe (>35%) injury. Trace injury

was observed up to 1,100 m downwind of

the facility. In 1987, fluoride injury was also

observed on the fluoride sensitive plants

tulip, hosta, canna lilies, Gladiolus, wild

grape and St. John's wort to a distance of

1.5 km NE of the facility. Fluoride levels in

unwashed maple foliage from 12 sites

around the facility were the second lowest

since 1974. The levels ranged from a

maximum of 46 μg g-1 DW in Manitoba

maple 300 m west of the facility, to 4 μg g-1

DW 750 m west of the facility, with a

consistent gradient of decreasing fluoride

levels with increasing distance. Levels varied

significantly from year to year depending on

uranium production. At the site 300 m east of

the facility, fluoride levels in maple foliage

(μg g-1 DW) ranged from a low of 20 in 1984

and 1986 to 1,075 in 1980 and 1,330 in

1977.

4.3.8 Tile Manufacturing

Niagara, Ontario

Soft suture disorder of peaches was reported

from three orchards within one-half mile of a

facility manufacturing field drainage tile in the

Niagara Peninsula of Ontario (Drowly et al.,

1963). Early maturing varieties of peaches

were the most susceptible to soft suture

disorder. In two of the orchards, severe leaf

drop occurred in June, with characteristic

fluoride injury on the leaves. Monthly

collections were made of peach leaves

during the summers of 1960 and 1961.

Fluoride levels in unwashed peach leaves

from the affected orchards averaged 40 to

50 μg g-1 DW compared to 27 μg g-1 DW

from control orchards. There was no

significant difference between the washed

and unwashed leaves, suggesting that

the emissions were mainly gaseous. The

application of lime sprays to the peach trees

reduced the incidence of soft suture.

4.3.9 Brick Manufacturing

Southern Ontario

Investigations of fluoride injury to and the

accumulation of fluoride in vegetation have

been carried out around a number of
Science Assessment Document for HF 31 CEPA/FPAC WGAQOG July 1996

brickworks in southern Ontario since the

early 1970s (Emerson, 1977, 1984, 1994a).

The zones of influence are generally

localized around these operations, with injury

on sensitive species such as wild grape,

eastern white pine and Manitoba maple

being moderate (11–35% injury on some

leaves) up to 300 m downwind and light (2–

10% injury on some leaves) up to 500 m

downwind. Fluoride levels in unwashed

maple foliage within 300 m of the brickworks

range from 100 to 360 μg g-1 DW, between

300 and 700 m downwind were 25 to 90 μg

g

-1 DW, and drop off to 5 to 15 μg g-1 DW at

1 km from the brickworks. The levels of

fluoride in washed foliage is marginally lower

or no different than unwashed foliage,

indicating that the majority of the fluoride

emissions from these brickworks are

gaseous in nature.

4.3.10 Fibreglass Manufacturing

Guelph, Ontario

Fluoride and boron injury to natural

vegetation and in Gladiolus biomonitoring

plots were studied around a fibreglass

manufacturing facility in Guelph, Ontario,

from 1969 to 1976 (Temple et al., 1978).

Fluoride and boron were used as a

component of the flux in the four glassmelting furnaces. Fluoride emissions went

from being uncontrolled in 1969 through a

series of control measures to total

elimination of fluoride from the

manufacturing process in 1972. In 1969,

severe fluoride injury on Manitoba maple,

silver maple and buckthorn leaves was

observed 150 m from the facility, with light

injury extending for another 150 m. In 1971,

with the reduction of fluoride but not boron

emissions, the extent of injury remained the

same, but boron injury became more

prominent in addition to fluoride marginal

necrosis. By 1972, when fluoride emissions

had been eliminated, fluoride injury

symptoms had been totally replaced by

boron injury. At the sampling station closest

to the facility, seasonal average fluoride

concentrations (μg g-1 DW) in washed silver

maple foliage went from 613 in 1969 and

1,600 in 1970 to 21 in 1973 and 26 in 1974.

Manitoba maple and buckthorn at other

locations showed a similar pattern. In 1969,

fluoride accumulation in foliage, as defined

by a seasonal average fluoride concentration

of greater than 50 μg g-1 DW, extended

2,000 m downwind of the facility. This

distance was reduced to 250 m in 1972 and

less than 30 m by 1974. There was no

significant difference between the washed

and unwashed fluoride content in the leaves

of all three species, indicating the emissions

were primarily gaseous.

4.3.11 Oil Refining

Mississauga, Ontario

The sudden appearance of injury on Scot's

pines up to 5 km from an Ontario oil refinery

was investigated (Linzon, 1978b). The

maximum amount of fluoride found in

severely injured Scot's pine needles was

16.3 μg g-1 DW, while the lowest amount of

fluoride found in the needles of control Scot's

pines was 1.3 μg g-1 DW. In addition, eastern

white pine, spruce, larch, plum, and

Manitoba maple displayed both marginal

necrosis and bifacial lesions in the central

portions of the leaves. A histopathological

study was conducted on the injured Scot's

pine needles (Linzon and Tung, 1976).

Cellular damage included collapsed

mesophyll cells, hypertrophied transfusion

parenchyma cells in the stele, a compressed

phloem and collapse of the endodermal ring
Science Assessment Document for HF 32 CEPA/FPAC WGAQOG July 1996

of cells surrounding the stele. The

combination of symptomatology, resistance,

and sensitivity of different species, the

chemical analysis results, and the

histopathological findings confirmed that the

injuries had been caused by an acute HF

fumigation.

4.4 INTERACTIVE EFFECTS OF HF

WITH OTHER GASEOUS

POLLUTANTS

Marcross corn that was fumigated

continuously with 0.56 μg m-3 and 191 μg m-3

SO2 for 12 days developed injury symptoms

that were greater than the sum of the effects

of the two contaminants acting independently

(Mandl et al., 1975). Similar results were

obtained by Murray and Wilson (1988a), who

reported that HF (up to 1.05 μg m-3) and SO2

(up to 271 μg m-3) synergistically increased

visible leaf injury in some species of

Eucalyptus. In a second series of experiments,

HF (0.38 μg m-3) and SO2 (267 μg m-3) applied

through the growing season were antagonistic

on leaf area, having less of an effect than

either compound alone (Murray and Wilson,

1988b). However, the effects of these

compounds on stem weight and above-ground

plant weight were synergistic. Applied

together, HF (1 or 3 μg m-3) and SO2 (260 or

780 μg m-3) both delayed the development of

common blight on red kidney bean and

resulted in smaller disease lesions (Laurence

and Reynolds, 1986).

Simultaneous fumigation of soybean plants

with 0.26 μg HF m-3 and 277 μg SO2 m-3

did not reduce bean yield to the extent of

SO2 fumigation alone (Murray and Wilson,

1990). The same treatments applied to

maize resulted in lower cob dry weights,

although kernel yield was not affected

relative to SO2 treatment alone. HF (0.27 μg

m

-3) reduced peanut yield, while SO2 (279 μg

m

-3) reduced the number of pods and kernels

per plant without significantly reducing total

yield. The interactive effect on plant

productivity of the two fumigants was less

than additive. Navy bean yield increased at

141 μg SO2 m-3; this stimulatory effect was

removed by treatment with 0.25 μg HF m-3.

Overall, Murray and Wilson (1990)

concluded that the effects of HF and SO2 are

often antagonistic since HF reduced the

effects induced by SO2 exposure; however,

the actual responses are species-specific.

In wheat and barley, as in the experiments

outlined above, the responses to joint

treatment with HF (0.38 μg m-3) and SO2

(130 or 267 μg m-3) were complex, but

mostly antagonistic (Murray and Wilson,

1988c). The effects of SO2 alone were often

counteracted by treatment with HF.

Fumigation of Marcross corn with HF

(1.5 μg m-3) and NO2 (2,280 μg m-3), with a

total dose of 2,280 μg HF days m-3 (which

approximates a 24-day treatment period)

resulted in less leaf damage than exposure

to the same HF dose alone (Amundson et

al., 1982). This was attributed to the

increased leaf resistance induced by NO2,

which likely resulted in reduced HF uptake

through the stomates.

Co-exposure to HF (1.0 μg m-3 for 4 hours

every second day over 8 days) and O3

(0.06 μl L-1 for 4 hours every second day

over 8 days, alternating with the HF

treatment) resulted in protection of 21-dayold corn plants from HF damage (chlorophyll

loss and membrane leakage), relative to

ozone treatment alone (MacLean, 1990).

Fluoride accumulation was enhanced in both

the HF alone and HF + O3 treatments;
Science Assessment Document for HF 33 CEPA/FPAC WGAQOG July 1996

however, HF alone had no effect on

chlorophyll levels or membrane integrity.

The complexity of responses of plants to

simultaneous or intermittent fumigations by

HF and other pollutants makes it impossible

at this time to derive reference levels for HF

in the presence of other gases. As shown by

the experiments discussed above, these

gases may act antagonistically, additively, or

synergistically even within the same plant,

depending upon the endpoint measured.
Science Assessment Document for HF 34 CEPA/FPAC WGAQOG July 1996
Science Assessment Document for HF 35 CEPA/FPAC WGAQOG July 1996

5 EFFECTS ON LIVESTOCK AND WILDLIFE

Review of the literature revealed a dearth of

information concerning the effects of

hydrogen fluoride on livestock and wildlife

which are exposed to hydrogen fluoride

mainly by the respiratory route. Some dermal

exposure may occur when hydrogen fluoride

mixes with water to form hydrofluoric acid.

Indirect exposure may occur through

ingestion of fluoride deposited on vegetation.

Generally, it was found that mammals are

less sensitive to the effects of hydrogen

fluoride than are plants. The difference in

sensitivity is approximately 1,000 times,

depending on the duration and manner of

exposure. For this reason, it is suggested

that the adverse effect on plants be used to

derive the reference level.

Airborne fluorine compounds will eventually

be deposited on and incorporated into, or

contaminate the surface of, plant tissues

eaten by animals. Indirect exposure to

airborne fluorine compounds is generally

more significant than direct exposure; that is,

ingestion is more pivotal than inhalation in

fluorosis. Therefore, consideration of an

ambient air guideline to protect livestock and

wildlife from the adverse effects of fluorine or

HF must take into account the inhaled

portion of the total dose of fluoride, the

portion ingested in food and water and the

portion absorbed through the skin.

 This review approaches evaluation of the

effects of HF in terms of its pharmacokinetic

effects (the effect of the body on the

chemical) and its pharmacodynamic effects

(the effect of the chemical on the body).

There were insufficient data available to

create a table showing effects following a

24-hour exposure to livestock and wildlife.

5.1 PHARMACOKINETICS

HF has the potential to cause significant

injury due to the unique toxicity of the

dissociated fluoride ion (Bertolini, 1992).

Upon contact with water, HF gas rapidly

forms hydrofluoric acid. This acid readily

gives up the reactive fluorine atom which,

with cations, forms a fluoride salt. Calcium is

rapidly altered to form calcium difluoride, an

almost insoluble fluoride salt. These two

chemical reactions account for the toxicity of

HF:

• acidic burns caused by hydrofluoric acid;

• sequestration of calcium as calcium

fluoride resulting in hypocalcemia;

• alteration of the calcium containing

hydroxyapatite crystal in bone, resulting in

fluorosis.

No pharmacokinetic studies of HF were

found for livestock and wildlife. However, the

kinetics of sodium fluoride (NaF) were

studied in a group of three adult ewes which

had been given NaF intravenously at three

dose levels (0.15, 0.375, and 0.75 mg kg-1

body weight). Data were analyzed using both

compartmental and non-compartmental

approaches. A three-compartment open

model was selected to describe the data.

Comparison of the different parameters

indicated the absence of change with dose

level, suggesting that fluoride behaved

linearly at the doses under study. The

half-life of the elimination was 2.57 ± 1.28

hours, the steady-state volume of distribution

was 0.26 ± 0.5 l kg-1, and the body clearance

was 0.105 ± 0.26 l kg-1 h-1.

Dermal absorption has not been described in

animals, but probably occurs in whole-body
Science Assessment Document for HF 36 CEPA/FPAC WGAQOG July 1996

exposure studies. As hydrofluoric acid,

dermal absorption is rapid and can be fatal in

humans (Bertolini, 1992) and possibly

animals. As a concentrated acid, hydrofluoric

acid causes burns. However, burns may take

several hours to develop at concentrations of

20 to 50%. During this time, a large dose of

fluoride ions has been absorbed. These

patients may die of hypocalcemia, a critical

situation caused by sequestration of calcium

by fluoride. This cationic imbalance can

cause death by heart failure in a manner

similar to the disease “milk fever”

(hypocalcemia) seen in periparturient cows in

veterinary medicine.

No studies on tissue distribution of fluoride

were found that dealt with HF; however, the

fluoride atom would be distributed primarily in

tissues high in calcium. Because of its

affinity to calcium, fluoride concentrations

are highest in bones and teeth following

chronic administration (Schupe et al., 1992).

Acute administration results in it binding to

blood calcium, hence the use of sodium

fluoride as an anticoagulant.

No elimination studies could be found;

however, most fluoride is eliminated by the

kidneys (Bartik and Piskac, 1981).

5.2 PHARMACODYNAMICS

In the real-world situation, acute poisoning

by fluorine, or HF, is rarely encountered in

domestic animals. Acute poisoning by

fluorides and hexafluoroplumbic salts, used

as pesticides, is more common (Bartik and

Piskac, 1981). There are a few reports of

accidental or intentional exposure to HF. For

the purposes of this review, they will be

classified by their temporal nature.

5.2.1 Acute Toxicity

The acute toxicity of HF in livestock and

wildlife has been poorly described. In a

toxicologic pathological study mainly based

on rodent exposure, dogs and rabbits were

exposed to concentrations of 6% to 50% of

the LC50 (median lethal concentration)

concentrations for rats (Rosenholz et al.

1963). Rat LC50 concentrations had been

established following exposure periods of

5, 15, 30, and 60 minutes to be

4,074 mg HF m-3 (4,970 ppm),

2,205 mg HF m-3 (2,690 ppm),

1,672 mg HF m-3 (2,040 ppm), and

1,074 mg HF m-3 (1,310 ppm), respectively.

The methodology did not describe the

method of exposure in enough detail to

determine whether whole-body or nose-only

exposure had occurred. The eye irritation

would indicate that probably whole-body

exposure had occurred.

Clinically, animals exposed to near-lethal

concentrations showed signs of conjunctival

and nasal irritation. Extensive nasal

secretions, lacrimation, pawing at the nose

and sneezing were noted. Non-lethal

exposures also revealed clinical

abnormalities. Rabbits (n=5) exposed to

50% of the rat (n=20) LC50 showed

respiratory distress lasting a few hours

following exposure, lacrimation, nasal

discharge, pawing at the nose, and

reddened conjunctivae. Pawing at the nose

continued for several hours following

exposure. The animals appeared depressed

and weak for at least 24 hours and appeared

sluggish for an additional day. Signs of nasal

and conjunctival irritation usually were not

seen after about four days (Rosenholz et al.,

1963).

Dogs (n=2) were exposed to approximately

25% of the rat LC50 concentrations and
Science Assessment Document for HF 37 CEPA/FPAC WGAQOG July 1996

showed blinking, periodic sneezing,

coughing, and signs of general discomfort

during the exposure. After removal from the

chamber, the dogs rubbed their noses and

bodies on grass, suggesting some skin

irritation (also indicating probable whole-body

exposure). No skin lesions were noted.

Although the cough disappeared within two

days, it reappeared upon exercise. All

coughing ceased after a week to ten days.

Haematological data did not show any

changes compared with pre-exposure data

and normal ranges for dogs (Rosenholz

et al., 1963).

The pathologic portion of the Rosenholz et

al. (1963) study was confined to the rats

exposed to HF. It should be noted that the

clinical signs seen in the rabbits and dogs

occurred at doses 1,000,000 times the

proposed ambient air quality reference level

for HF.

5.2.2 Chronic Toxicity

Chronic HF toxicity has not been well

characterized owing to the nature of the

reactive molecule , which does not remain in

the body as HF very long. For all intents and

purposes, chronic HF toxicity should be

considered as chronic fluoride toxicity.

Chronic fluoride toxicity has been well

reviewed elsewhere and will not be for the

core of this review (Agency for Toxic

Substances and Disease Registry, 1993;

U.S. National Academy of Sciences, 1974).

A case report of HF toxicosis in camels is

foound in Karram and Ibrahim (1992). These

workers evaluated the hemograms from 114

camels at various distances from a

super-phosphate factory in Egypt. The

authors took and analyzed blood sera and

whole blood to determine fluoride levels and

haematological parameters, and state that

elevated mean corpuscular volume (MCV)

values correlated with levels of sodium

fluoride. They also claim that decreased total

erythrocytes (RBC), haemoglobin (Hb),

packed cell volume (PCV), and mean

corpuscular haemoglobin (MCH) levels were

associated with the elevated MCV values.

Evaluation of the data showed that the MCV

values were elevated in comparison to

control animals, when mathematically

compared. However, there were no groups

that fell out of the normal range for each

parameter, indicating that the mathematical

differences were not biologically significant.

Serum fluoride levels of the camels that

received the greatest exposure (1.56 mg m-3;

1.90 ppm) were seen to be ten times that of

the control group (0.09 mg m-3; 0.11 ppm).

The assay methodology is not detailed, nor

are the exact criteria for the definition of

fluorosis in the camels. For these reasons,

this paper should not be considered in the

reference level derivation for ambient HF

concentrations.

5.2.3 Developmental Toxicity,

Reproductive Effects and

Carcinogenesis

No studies were found that dealt with the

developmental, teratological, reproductive or

carcinogenic effects of HF in livestock and

wildlife.

5.2.4 Fluorides

Fluoride salts are present in most animal

foods and occur naturally in many water

supplies (Schupe et al., 1992). Fluoride salts

enter the mammalian body mainly through

ingestion, and may be passed on to the fetus

(Schupe et al., 1992). Usually only small
Science Assessment Document for HF 38 CEPA/FPAC WGAQOG July 1996

quantities enter via the respiratory tract as

dusts (Ontario Ministry of Labour, 1983).

Absorption of fluoride salts through the skin

is insignificant (Cass, 1961). The U.S.

Environmental Protection Agency (cited in

World Health Organization, 1984) lists the

most common sources of excessive fluoride

salts for livestock as follows:

• forage crops, usually the major source of

an animal's diet, which have been

contaminated by HF and fluoride salt

emissions, or wind-blown or rain-splashed

soil with a high fluoride salt content;

• water with a high fluoride content;

• feed supplements and mineral mixtures

that have not been properly defluorinated;

• forage crops grown in soils with a high

fluoride salt content.

The first of these sources is of primary

interest in the present context. The most

frequent causes of excessive fluoride salt

concentration in vegetation are industrial

emissions of HF and other fluoride salts.

Volcanic eruptions releasing HF can also

result in high concentrations of fluoride salts

in plants (Kessabi et al., 1984). The earliest

report of this phenomenon is from Icelandic

literature following volcanic eruptions about a

1,000 years ago (Roholm, 1937), but similar

effects were reported following the eruptions

of Mount Hekla in 1963. Eruptions in the

Lonquimay volcanic complex in the Andes

were the cause of bovine fluorosis in the

southern part of Chile (Araya et al., 1990).

The fluoride content of the ash was 75 to

100 μg g-1 and fluoride contaminated forage

was the main route of cattle intoxication.

Wildlife, such as deer, are also at risk of

contamination by fluoride-containing

industrial emissions, often detected by

changes in the skeletal system (Machoy

et al., 1991).
Science Assessment Document for HF 39 CEPA/FPAC WGAQOG July 1996

One of the more aggressive forms of

intoxication is the inhalation and ingestion of

dust containing fluoride, since this causes an

abrasive local action on the respiratory and

digestive systems in addition to the usual

systemic effects (Bartik and Piskac, 1981).

Injury caused by fluoride salts (fluorosis) in

livestock develops progressively when total

fluoride dietary concentrations exceed 20 to

30 μg g-1 (U.S. National Academy of

Sciences, 1974). Here the fluorine atom

binds to calcium, rendering the calcium

atoms unavailable for their normal bodily

functions. Diagnosis of fluorosis is based on

clinical observations, especially of dental and

skeletal lesions, lameness, biopsy of tail

bones, determination of fluoride in the total

diet, effects on appetite, decreased milk

production or body growth and, where

applicable, post mortem examination. The

simultaneous administration of aluminium

sulphate has been reported to alleviate

dose-related fluorosis (Kessabi et al., 1986).

Fluoride crosses the bovine placenta, which

acts as a partial barrier (Schupe and Bagley,

1992). Pharmacokinetics of fluoride (see

section 7.1) have been determined in sheep

(Joseph-Enriquez et al., 1990). The effects

of fluorosis have been described in cattle

(Schupe et al., 1992) and camels (Karram

and Ibrahim, 1992).

Animals differ in their susceptibility to

ingestion, as shown in table 7. Ingestion

would represent the indirect route of

exposure to airborne fluorine compounds.

Based on the previous review, the lowest

level of fluoride in forage or feed which

appears to lead to adverse effects is

40 μg g-1 DW in the most sensitive species.

The atmospheric concentration of HF which

would lead to such levels appear to be 0.33

to 1.3 μg m-3 fluorides for 30 days.

Table 7 Susceptibility of animals to

fluoride by ingestion

Animal Fluoride feed levels

affecting performance

(μg g-1)

Beef or dairy

heifers

40

Mature beef or

dairy heifers

50

Finishing cattle 100

Feeder lambs 150

Breeding ewes 60

Horses 60

Growing dogs 100

Finishing pigs 150

Breeding sows 150

Growing or boiler

chickens

300

Laying or

breeding hens

400

Turkeys 400

Source: World Health Organization, 1984

5.3 CONCLUSION

In addition to the dearth of information on

effects at different exposure levels, time of

exposure does not support the development

of a 24-hour exposure reference level for the

protection of livestock and wildlife. From the

weak chronic study data, it appears as

though a continual exposure on mammals

should not exceed 7 mg m-3. This

concentration is more than three orders of

magnitude greater than that recommended

for the HF reference level based on the

effects of HF on plants.

Airborne fluorine compounds will eventually

be deposited on and incorporated into, or
Science Assessment Document for HF 40 CEPA/FPAC WGAQOG July 1996

contaminate the surface of, plant tissues

eaten by animals. Indirect exposure to

airborne fluorine compounds is generally

more significant than direct exposure; that is,

ingestion is more pivotal than inhalation in

fluorosis. Therefore, consideration of an

ambient air guideline to protect livestock and

wildlife from the adverse effects of fluorine or

HF must take into account the inhaled

portion of the total dose of fluoride, the

portion ingested in food and water, and the

portion absorbed through the skin.

HF gas is a potent, acute toxicant when

animals are exposed to large quantities

directlyly via the respiratory route. The

chemical properties of the compound

accounts for its pharmacodynamic

properties: it mixes with water to form a

strong acid resulting in burns, and it binds to

calcium resulting in sequestration of calcium

and alteration of bone calcium (chronic

exposure). As HF rapidly becomes a fluoride

salt, the majority of the toxicity issues can be

considered under the evaluation of the

toxicity of fluorides. No chronic exposure

studies were available for HF.

It is concluded that while plants are more

likely to be affected at lower concentrations

of HF than livestock and wildlife, protection

of farm and wild animals from fluorosis can

be achieved by implementing a maximum

level of fluorides in feed and forage.
Science Assessment Document for HF 41 CEPA/FPAC WGAQOG July 1996
Science Assessment Document for HF 42 CEPA/FPAC WGAQOG July 1996

6 EFFECTS ON EXPERIMENTAL ANIMALS

There are a number of reports on the effects

of hydrogen fluoride on experimental

animals, usually rodents.

6.1 ACUTE TOXICITY

This section includes results from studies

where animals were exposed to HF for 24

hours or less. HF and other gaseous

fluorides such as tetrafluoride induce

respiratory tract damage. If this damage is

not in itself lethal, systemic intoxication may

follow (World Health Organization, 1984).

Five guinea pigs and five rabbits died in 0.5

and 1.5 hours, respectively, after exposure

to 540 mg m-3 HF (660 ppm). When five

guinea pigs and five rabbits were exposed to

205 mg m-3 HF (250 ppm), they died within

1.0 and 3.0 hours. All animals showed

severe signs of irritation from the start of the

experiment, with increasingly laboured

breathing. Autopsy showed ulceration of the

upper respiratory tract and of the cornea of

the eyes. The lungs were hyperaemic and

edematous. At 40 mg m-3 (50 ppm), five

guinea pigs died in two hours, whereas the

five rabbits displayed severe signs of

physical distress after three hours of

exposure. At a concentration of 25 mg m-3

(30 ppm), guinea pigs died after a day, while

rabbits were in such poor condition that they

were sacrificed. Continuous exposure at 8

mg m-3 (10 ppm) for 5 days was not fatal to

either species. In addition to laboured

breathing, the guinea pigs showed only slight

irritation of the eyes (Ronzani, 1909, cited in

Heitman, 1976).

Machle et al. (1934) reported that exposure

to 1,000 to 1,500 mg HF m-3 for five minutes

caused death in a significant proportion of

the rabbits and guinea pigs exposed.

Damage to liver, kidneys and lungs was

observed in animals exposed to 245 mg m-3.

Dipasquale and Davis (1971) reported the

lethal concentration for 50% of the exposed

population (LC50) for a five-minute exposure

to HF for rat and mouse to be 14,400 and

5,000 mg F- m-3, respectively.

The 60-minute LC50 values for rats and mice

were reported to be 1,100 and 270 mg F- m3

, respectively (Wohlschlagel et al., 1976).

When rats were exposed through inhalation

to HF for 5, 15, 30, or 60 minutes, the

LC50s were 4,060, 2,200, 1,670 and

1,070 mg HF m-3, respectively. The LC50

for guinea pigs with an exposure time of

15 minutes was 3,540 mg HF m-3. Irritation

of the mucous membranes of the eyes and

nose, weakness, and a decrease in body

weight was observed in the HF-exposed

animals (World Health Organization, 1984).

Acute inflammation and focal necrosis of the

nasal mucosa, irritation of the skin, necrosis

of the renal tubular epithelium, congestion of

the liver and vacuolisation of its cells and

myeloid hyperplasia of the bone marrow

were found histologically (World Health

Organization, 1984).

The HF LC50 value is three to five times

higher than the fluorine LC50 value in rats. In

general, the gradient of susceptibility in

laboratory rodents is mice>rats>guinea pigs

(Rosenholtz et al., 1963; Agency for Toxic

Substances and Disease Registry, 1993).

Sub-lethal inhalation exposure of rats and

mice to fluorine or HF affects the respiratory

system (mild congestion, disperse), liver

(coagulation necrosis and cloudy swelling),

kidney (coagulation and necrosis) and

mucous membranes (irritation of eyes and
Science Assessment Document for HF 43 CEPA/FPAC WGAQOG July 1996

nose) (Keplinger and Suissa, 1968). In this

study, rats, mice and guinea pigs, rabbits

and dogs were exposed to fluorine for 5

minutes at 820 mg m-3 (1,000 ppm), 15

minutes at 57 mg m-3 (70 ppm), 30 minutes

at 45 mg m-3 (55 ppm), or 60 minutes at 37

mg m-3 (45 ppm). This non-linear effect

illustrates the difficulty in extrapolating to

24-hour ambient concentrations. These

sublethal concentrations did not result in any

significant differences in haematological

parameters. Gross evaluation of the animals

sacrificed serially after exposure showed that

the lungs had the greatest change of any

organ (the nasal passages were bypassed).

Lesions seen included congestion,

petechiation, and diffuse consolidation.

These lesions decreased in severity with

time after exposure. The interpretation of

these lesions was not given by the authors,

although their appearance is typical of

diffuse bronchiolar and alveolar damage.

Histopathology revealed that coagulation

necrosis was present in the lower airways

and the alveoli, consistent with hydrofluoric

acid damage. The explanation for the

hepatic coagulation necrosis is more difficult

since the zonal nature of the lesion was not

given. If hydrofluoric acid had been

swallowed in substantial quantities, then

absorption of the compound into the portal

tree could have resulted in zonal coagulation

necrosis. The anticipated distribution of this

necrosis would be periportal in nature.

The acute toxicity of five-minute exposure to

HF was studied also by Higgins et al. (1972)

in rats and mouse in an observational period

of seven days. The five-minute LC50 was

14,900 mg m-3 HF (18,200 ppm) and for mice

5,120 mg m-3 HF (6,247 ppm). The same

LC50s for mice and rats were also reported

by McEwen and Vernot (1971). For a 60-

minute exposure, the LC50 values for mice

and rats were 374 mg m-3 and 792 mg HF m3

, respectively (Vernot et al., 1977). McEwen

and Vernot (1971) reported that, following a

5-minute exposure to HF, most of the

exposed animals experienced pulmonary

edema of varying severity, and pulmonary

haemorrhage was a common finding in

animals that died during or shortly after

exposure to HF at levels above the LC50

value.

Inhalation of HF constitutes the most

common route of exposure; however, there

are data to suggest that absorption does not

only occur at the level of the alveolar

epithelium. In a study of the regional

disposition and absorption of inhaled HF

(36 to 176 mg F m-3) in male Long-Evans

rats, it was seen that virtually all inhaled HF

was deposited in the upper respiratory tract.

Less than 0.1% was found to pass into the

lungs thus leaving 99.7% absorbed in the

upper respiratory tract. The authors

concluded that although the upper

respiratory tract serves to protect the lower

respiratory tract in rats, most of the

absorption into the blood stream results from

absorption at the lower site (Morris and

Smith, 1982).

In another experiment (Stavert et al., 1991),

biologically significant damage to the middle

and lower airways occurred when male

Fischer-344 rats were forced to breathe

approximately 1,066 mg m-3 (1,300 ppm) of

HF vapour for five minutes. These animals

were intubated with endotrachial tubes, thus

bypassing the nasal cavity. It is clear from

the above experiments that the nasal cavity

protects the lower airways from the corrosive

effects of gaseous HF, and acts as the major

site of absorption of this compound.

The pathology seen in the rats acutely

exposed to HF can be attributed to the
Science Assessment Document for HF 44 CEPA/FPAC WGAQOG July 1996

corrosive nature of the compound, once it

comes into contact with the water associated

with the exposed epithelium and forms

hydrofluoric acid. In the upper respiratory

tract severe epithelial necrosis,

fibrinopurulent exudate and submucosal

inflammation indicate that a full thickness

epithelial burn had occurred in the nasal

cavity of rats treated with 1,066 mg m-3

(1,300 ppm) HF for 30 minutes (Stavert et

al., 1991).

Mild suppurative tracheitis was present in the

proximal trachea of these treated animals

(Stavert et al., 1991). This less severe lesion

decreases in severity the more distal it is

from the nose. This may indicate a decrease

in the concentration of HF as it is removed

from the air space higher up the airway.

The lungs also showed mild irritation,

characterized by infiltration of neutrophils in

the alveoli. There was no description of

necrosis of alveolar epithelium, known for its

exquisite sensitivity to insult.

6.2 SHORT-TERM TOXICITY

The only gaseous fluoride exposure studies

that have been reported are for HF, and of

those few reports the exposure durations

were one day to one year.

Fifteen rabbits, 21 guinea pigs and four

pigeons were exposed to HF at 8 mg m-3

(10 ppm) for two 3-hour periods per day

for 31 days. During this period, two rabbits,

seven guinea pigs and one pigeon died.

At autopsy, opacity of the cornea with

ulcerations, lesions of the nasal mucous

membranes, emphysematous lungs,

bronchopneumonitis, and interstitial

pneumonitis were found. The autopsy of one

of the rabbits surviving the exposure periods

showed similar, but less severe, pathologic

findings. All surviving animals had lost up to

23% of their original weight and had severe

anemia. After five HF-exposed guinea pigs

had been immunized, they showed a marked

decrease in the production of specific

antibodies, and their resistance to bacterial

infection in the lungs was reduced. While

exposed to HF, the animals were less

resistant than controls to the effects of

inoculation with diplococous and tuberculous

bacilli; the opposite was true for anthrax

(Ronzani, 1909, cited in Heitman, 1976).

Nevertheless, these results seem to indicate

an immunotoxic effect of airborne HF.

Further studies by Ronzani (1909, cited in

Heitman, 1976) using HF concentrations of

6, 4, and 2.5 mg m-3 (7.5, 5, and 3 ppm)

established 2.5 mg m-3 (3 ppm) as the

NOAEL (No Observable Adverse Effect

Level), because in a 30-day study with

16 rabbits, 20 guinea pigs and 3 pigeons,

exposure to HF did not cause any pathologic

changes.

Machle and Kitzmiller (1935) reported that no

externally obvious adverse effects were

noted in rabbits, guinea pigs and Rhesus

monkeys exposed to 15.2 mg HF m-3 for a

total of 309 hours (six to seven hours per

day over about 10 weeks, observed for up to

eight more months post-exposure). Two

guinea pigs became sick and died after

134 and 160 hours of exposure. Both of

these animals showed liver and lung damage

(one had pulmonary haemorrhage), and one

had kidney damage. The surviving animals

were normal in behaviour and appearance,

but had decreased growth rates. Some had

decreased erythrocyte counts. At necropsy,

these rabbits and guinea pigs exhibited

varying degrees of lung, liver and kidney

damage. The Rhesus monkeys revealed

kidney damage only. The authors indicate

that the lower limit of toxic HF concentrations
Science Assessment Document for HF 45 CEPA/FPAC WGAQOG July 1996

in air lies between 30 and 2.5 mg m-3 based

on older studies (Ronzani, 1909, cited in

Heitman, 1976; Flury and Zernik, 1931).

Stokinger (1949) performed a toxicity study

in which 29 rats, 20 mice, 20 guinea pigs,

18 rabbits and 4 dogs were exposed to

gaseous HF at concentrations of 25 and

7 mg m-3 for six hours per day, six days per

week for five weeks. A second group of

animals (15 rats, 20 mice, 10 guinea pigs,

10 rabbits and 5 dogs) were exposed to

7 mg HF m-3 for the same period.

Subcutaneous haemorrhages, particularly

around the eyes and on the feet, were

observed in rats and, to a lesser degree, in

mice. In dogs, an inflammation of the scrotal

epithelium was seen after three days’

exposure. These effects were observed

mainly at the 25 mg HF m-3 exposure level,

although haemorrhagia to lesser extent was

also noticed on the feet of rats exposed to

7 mg HF m-3. Death occurred only at

25 mg HF m-3 in all rats and mice. Deaths

occurred in rats throughout the entire

exposure period, while all mice died by

17 hours of exposure. At the 25 mg HF m-3

concentration, rats showed pronounced

weight loss; rabbits showed a slight loss,

dogs showed none while guinea pigs, after a

consistent gain, lost weight following the third

week of exposure. No species showed any

significant effects on weight at the 7 mg m-3

level. No effects were noted on bloodcalcium alkaline phosphatase or serum

proteins in dogs and rabbits. There was a

significant increase in blood fibrogen level in

dogs and rabbits exposed to 25 mg HF m-3,

while the prothrombin level remained normal.

At autopsy, 27 out of 44 animals exposed to

25 mg HF m-3 showed haemorrhages and

edema of the lungs. Degenerative testicular

changes and ulcerations of the scrotum

were found in four dogs. In rats, renal

cortical degeneration and necrosis were

noted in 27 of 30 animals. At the 7 mg HF m3

 level, localized haemorrhagic areas in

the lungs were observed only in one dog.

A progressive increase of fluoride in the

animal bones was detected at the

25 mg HF m-3 exposure level, from 25 to

95 hours. The fluoride concentration in the

rats’ teeth increased 300%. A somewhat

smaller increase was found in the femur. In

maxillary and mandibular bone of the dogs,

increases of fluoride concentrations ranged

from 200 to 300%. The fluoride

concentration of animal bones exposed to 7

mg HF m-3 for 166 hours was somewhat

lower than that of in the high exposure level.

According to Heitman (1976) for this study at

almost equal HF concentrations times

exposure time (HF dose), the fluoride

deposition in bone and teeth was

approximately the same. In this study of

Stokinger (1949) a distinct NOAEL (No

Observable Adverse Effect Level) could not

be established, as some slight haemorrhagic

changes in the lung were still observed at the

lowest level tested (7 mg HF m-3). Stokinger

et al. (1950) reported the effects of airborne

HF on 29 rats exposed 6 hours per day, 5

days per week at an average concentration

of 8 mg HF m-3 for total of 124 hours

(approximately 4 weeks). In this study no

adverse effects due to exposure to HF were

observed, indicating that the NOAEL could

be 8 mg HF m-3 at that exposure regime for 4

weeks. However, no higher exposure level

were tested in this study.

Changes in the lipoid, cholesterol and total

lipid content in the lungs and liver have been

studied in 4 series of experiments on

337 white rats, exposed to HF, H2S and SO2

for 4 hours daily during 4 months. Isolated

and combined effects of theses gases

induced phasic changes of varying degree,
Science Assessment Document for HF 46 CEPA/FPAC WGAQOG July 1996

depending on the gas concentration. The

lipid content in the lungs was reduced under

the effect of gas in low concentrations, and

in the liver it increased under the effect of HF

(and decreased under the effect of H2S).

A NOAEL in this study is not indicated

(Aitbaev, 1984).

Inhaled HF (10 mg m-3 for 14 days) increases

plasma cholesterol levels very significantly in

normal guinea pigs and in guinea pigs with

chronic latent vitamin C deficiency. Ascorbic

acid deficiency significantly increased

plasma cholesterol levels in exposed animals

and controls. But ascorbic acid deficiency

produced an increase in cholesterol less

important than HF inhalation. These results

showed that vitamin C deficiency and HF

inhalation both produce an increase of

cholesterol level, but they do not interact.

The mechanism of cholesterol increase has

been investigated. In HF inhalation, the

activity of cholesterol 7 alpha-hydroxylating

system containing cytochrome P450 does not

decrease in the liver microsomes (Dousset

et al., 1984).

Two experiments studied the effect of HF

inhalation on lipid metabolism in guinea pigs

(Phillibert et al., 1991). In the first

experiment, control was established before

guinea pigs were exposed to 7 mg HF m-3 for

96 hours, following which the effects were

measured on their plasma cholesterol, nonesterified fatty acids and cyclic AMP.

Exposed guinea pigs showed no weight

change, but their plasma fluoride

concentration increased significantly, from

8.5 to 203.2 μmol L-1 . Mean plasma

cholesterol and free fatty acids also

increased significantly. As well, plasma

cAMP had increased, which could be the

cause of changes in lipid parameters.

However, experiments with theophylline

showed that the increase in plasma

cholesterol was mediated by the increase of

plasma.
Science Assessment Document for HF 47 CEPA/FPAC WGAQOG July 1996

The second experiment consisted of three

groups with 14 guinea pigs per group: a

control group, a group treated with orally

administered simvastatin (a drug inhibiting

the activity of beta-hydroxy beta- methyl

glutamyl CoA {HMG-CoA-reductase}, which

regulates the biosynthesis of cholesterol),

and a group exposed to 7 mg m-3 for 96

hours. These studies provide no information

to establish NOAEL. It was demonstrated

that inhaled HF modifies the biosynthesis

regulation of cholesterol by an effect on the

HMG-CoA reductase activity.

6.3 LONG-TERM TOXICITY AND

CARCINOGENICITY STUDIES

There are very few long-term toxicity studies

of gaseous HF. The studies involve

exposures for periods greater than one year.

In one study, guinea pigs and rabbits were

exposed to as little as 24.5 mg HF m-3 for six

hours daily for a total of 41 hours; they were

autopsied 18 hours post exposure. There

were no deaths among the animals left alive

and observed for one year (Machle and

Kitzmiller, 1935; Machle et al., 1934).

In a long-term inhalation study, 50 guinea

pigs were exposed to an atmosphere varying

from 125 to 203 μg HF m-3 for 18 months in

order to study the effects on the metabolism

of myoardial cells and biochemical serum

parameters indicative for cardiac cell

damage. An unexposed group of guinea pigs

served as control. In the study there were

also interim kills at six and 12 months. After

six months of exposure to HF a significant

increase in the oxygen consumption of

myocardial cells, whereas a strong significant

decrease in oxygen consumption was

observed after 12 and 18 months of

exposure. In addition, after 12 and 18

months of HF exposure an increase in both

total lactate dehydrogenase (LDH) and

creatinine-kinase (CK) and in the myocardial

LDH and CK-MB isoenzymes was detected.

(Bourbon et al., 1979). From these results, it

is indicated that a long-term exposure to 125

to 203 μg HF m-3 will cause cardiotoxic

effects, and thus a NOAEL cannot be

established.

In another long-term inhalation study, 50

guinea pigs were subjected to an

atmosphere containing 150 μg HF m-3 for 18

months in order to evaluate the histological

and biochemical effects on kidney

functioning. Unexposed guinea pigs were

used as a control group. In this study there

were also interim kills at six and 12 months.

The only effect observed in the HF-exposed

guinea pigs was a transient increase of

calciurea and phosphaturea. The authors

concluded that inhaled HF did not cause any

alteration of kidney function in either the

biological or histological parameters of the

kidney and its function (Rioufol et al., 1982).

This study did not provide a real NOAEL.

No animal bioassays have been reported on

the potential carcinogenicity of inhaled

fluorides (Thiessen, 1988).

Because of the nature of the compound,

chronic low-level exposure to HF can be

treated as being equivalent to fluoride salts.

Table 8 lists reported NOAELs and LOAELs

(Lowest Observable Adverse Effect Levels)

for mice and rats. More detailed information

about fluoride salts can be found in Agency

for Toxic Substances and Disease Registry

(1993), National Research Council (1971)

and Drury et al. (1980). Longer-term effects

of HF have been investigated in rats, mice,

guinea pigs, rabbits and dogs. All species

were exposed to 7 or 24 mg m-3 HF for six

hours per day, six days per week for 30 days
Science Assessment Document for HF 48 CEPA/FPAC WGAQOG July 1996

(Stokinger, 1949). Marked species

differences were noted. All rats and mice

exposed to 24 mg m-3 died, but no guinea

pig, rabbit or dog exposed at this

concentration died. No animal of any species

died following exposure to 7 mg m-3.

Table 8 Estimates of NOAEL and LOAEL for mice and rats

NOAEL (mg F2 m-3) LOAEL (mg F2 m-3)

Mice Rats Mice Rats

Mean + SD* 106 + 67 75 + 31 153 + 75 146 + 65

Range 23 - 263 42 - 132 45 - 303 71 - 263

Source: Agency for Toxic Substances and Disease Registry, 1993

* Standard deviation

No Observable Adverse Effect Levels

(NOAELs) and Lowest Observable Adverse

Effect Levels (LOAELs) for rats and mice

have been estimated (Agency for Toxic

Substances and Disease Registry, 1993),

and are presented in table 8. These data

refer to lethality. The NOAELs quoted are for

the following endpoints:

• rat, rabbit and dog haematology

(24 mg m-3 for 6 hours per day,

6 days per week),

• renal disease in rats (7 mg m-3 for 6 hours

per day, 6 days per week),

• neurological effects (0.03 mg m-3 for

5 months undisclosed exposure), and

• testicular degeneration (7 mg m-3 for

6 hours per day, 6 days per week for

30 days).

The equivalent information is not available

for livestock or other animals. The latter

raises the issue of robustness of the

reported concentrations because of changes

in chemical methods.

The use of lethality data from experimental

animals may overestimate the practical

threshold of the effects of fluorine and HF

since the slopes are steeper than for irritation

and other biological endpoints (Alexeeff

et al., 1993).

6.4 REPRODUCTIVE TOXICITY,

TERATOLOGY AND

GENOTOXICITY STUDIES

With the exception of a study in Drosophila,

no specific genotoxicity experiments with

airborne HF or other fluorides are reported.

Several authors have suggested the

potential mutagenicity of either HF or sodium

fluoride (NaF) to lower (bacteria, yeasts) and

higher plants (Drosophila) or mammals

(Caspary et al., 1987; Cole et al., 1986;

Gerdes, 1971; Gerdes et al., 1971; Mitchell

and Gerdes, 1973; Mohamed, 1977;

Mohamed and Kenner, 1969; Tsutsui et al.,

1984 a, 1984b, 1984c; Voroshilin et al.,

1973, 1975). On the other hand, Leonard et

al. (1977) found no increase in chromosome

aberrations in the leucocytes of cattle with

chronic fluoride poisoning, nor did Voroshilin

et al. (1973) or Obe and Slasic-Erben (1973)

in human leucocytes treated in vitro with 18

and 54 mg L-1 NaF. Temple and Weinstein

(1978) were unable to demonstrate

mutagenicity of HF in tomato plants. Martin
Science Assessment Document for HF 49 CEPA/FPAC WGAQOG July 1996

et al. (1979) found no evidence for increased chromosome aberration in mice following

exposure to NaF administered orally, nor did

they find NaF to be mutagenic in a bacterial

(Salmonella) mutagenesis assay and it did

not induce gene inversion in Sacheromyces

cerevisiae. A review by the International

Agency for Research on Cancer (1982)

found that NaF is not mutagenic in

Salmonella or Drosophila, and both the US

EPA (Federal Register, 1985) and the Safe

Drinking Water Committee (1977) concluded

that the mutagenicity of fluoride in humans

has not been demonstrated (Thiessen,

1988). Little or no effect was noted on

chromosomes when mouse oocytes were

exposed in vitro to a fluoride concentration of

200 mg L-1 in media for up to 14 hours.

Sheep and cow oocytes were unaffected by

a concentration of 100 mg L-1 in media for 24

hours (Jagiello and Lin, 1974). Mohamed

and Chandler (1977) reported that the

number of cells from bone marrow or

spermatocytes with chromosomal

abnormalities increased in mice with a

fluoride dose in drinking-water of 1 mg L-1 or

more. Owing to various inconsistencies and

lack of proper double-blind procedures, the

results of Mohamed and Chandler (1977)

have been questioned (Victoria Committee,

1980; World Health Organization, 1984).

6.5 CONCLUSION

With the paucity of data in experimental

animals, it becomes difficult to establish air

quality objectives . Furthermore, the

chemical analytical procedures used in the

older references (i.e., pre-1950s) may not be

as precise or accurate as today's methods.

At best, the conclusions can only address

acute exposure to HF. Human sensory levels

may be more sensitive than animal studies in

establishing tolerable levels for brief human
Science Assessment Document for HF 50 CEPA/FPAC WGAQOG July 1996

exposures (Rosenholz et al., 1963). For

example, it appears that humans (Largent,

1961; Machle et al., 1934) might be more

sensitive than rats (Keplinger and Suissa,

1968; Wohlschlagel et al., 1976) to the

irritant effects of fluorine or HF, perhaps by

an order of magnitude.
Science Assessment Document for HF 51 CEPA/FPAC WGAQOG July 1996

7 EFFECTS ON HUMAN HEALTH

Acute exposure to gaseous fluoride is rare in

a non-occupational setting. Hydrogen

fluoride and fluorine are extremely toxic,

posing immediate danger to health and life.

Both gases can cause severe respiratory

damage or skin burns on contact. Skin burns

and respiratory damage caused by hydrogen

fluoride are the only toxic effects of hydrogen

fluoride that are not attributable solely to the

action of the fluoride ion. Systemic fluoride

poisoning usually occurs from hydrogen

fluoride absorbed via the lungs or the skin

(Thiessen, 1988).

Following exposure to gaseous fluorides and

hydrogen fluoride by either inhalation or

dermal contact, systemic effects are based

on the fluoride absorbed and in circulation in

the body. Under these circumstances,

systemic toxicity parallels the toxicity of

ingested fluoride. Where possible, this

discussion is limited to aspects of the toxicity

of gaseous hydrogen fluoride. A more

complete overview of fluoride toxicity can be

found in several extensive reviews (World

Health Organization, 1984; Thiessen, 1988;

Government of Canada, 1993).

A comparison of the properties of hydrogen

fluoride with those of other hydrogen halides

indicates deviations from expected values

because of polymerization of the hydrogen

fluoride molecule. The degree of

polymerization varies depending on the

partial pressure of the hydrogen fluoride and

the temperature. At airborne concentrations

of hydrogen fluoride at or near the

recommended limits in the workplace, the

partial pressure will be low enough that the

polymerization of hydrogen fluoride is

negligible. In this situation, it is probable that

the molecular weight of hydrogen fluoride is

20 (Heitman, 1976). To account for any

uncertainty in the figures for hydrogen

fluoride and other airborne fluorides, the

environmental limits are expressed in mg m3

 instead of in ppm. Especially at high

exposure levels, the best way to express the

concentration for review of toxicological

studies is in mg m-3 if possible (if given).

When units for airborne hydrogen fluoride

are converted from ppm to mg m-3 in this

report, it is assumed that airborne hydrogen

fluoride exists as a monomer. If it is clear

that the data refer to hydrogen fluoride, a

conversion factor can be applied, and these

calculated figures are indicated in

parentheses. If total gaseous fluoride is

indicated, it is not possible to express the

units other than as given, unless the

molecular weight or a conversion factor is

provided by the authors.

7.1 PHARMACOKINETICS

7.1.1 Absorption

Inhaled fluorides consist primarily of

hydrogen fluoride and particulate fluorides,

both of which can be deposited in the

respiratory tract (World Health Organization,

1984). Hydrogen fluoride, which is highly

soluble, is rapidly taken up in the upper

respiratory tract (World Health Organization,

1984) and quickly 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% of inhaled hydrogen

fluoride is absorbed (Machle and Largent,

1943; Thiessen, 1988). Absorption of inhaled

fluorides is dependent on several factors,
Science Assessment Document for HF 52 CEPA/FPAC WGAQOG July 1996

including the chemical nature of the fluoride

and of other substances that may have been

co-ingested or co-inhaled. Fluoride from

inhaled dust is absorbed as rapidly as from

inhaled hydrogen fluoride, but the total

fluoride is less than from gaseous fluorides

(Collings et al., 1952). Hydrogen fluoride is

readily absorbed through the skin of

individuals accidentally exposed in the

workplace, leading to hydrofluoric acid burns

(Burke et al., 1973; Tepperman, 1980; World

Health Organization, 1984).

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 hydrogen fluoride (Whitford et al.,

1976; Guttknecht and Walter, 1981; Whitford

and Pashley, 1984). At physiological pH (in

blood, intracellular fluid or mucus), fluoride

from any source exists primarily as the

fluoride ion (F ), although a small amount of

molecular hydrogen fluoride exists in

equilibrium with the ion. The fate and effects

of absorbed inorganic fluorides are

essentially independent of the fluoride

source (Thiessen, 1988).

7.1.2 Distribution

Once absorbed by the human body after

inhalation, fluoride is transported through the

body via the bloodstream and is then

retained in the tissues, predominantly the

skeleton, or excreted, mainly in the urine

(World Health Organization, 1984). About

75% of the fluoride in blood is present in the

plasma; the rest is found mainly in or on the

red blood cells (Carlson et al., 1960a, 1960b;

Hosking and Chamberlain, 1977; World

Health Organization, 1984; Thiessen, 1988).

Both the uptake of fluoride in calcified

tissues and urinary excretion are fast

processes (Collings et al., 1952; Charkes et

al., 1978; World Health Organization, 1984;

Thiessen, 1988). Approximately 35–48% of

systemically absorbed fluoride from any

source is retained in the human body (Hodge

and Smith, 1965; World Health Organization,

1984; Thiessen, 1988). At low fluoride

uptake levels (non-occupational, <4.0–5.0

mg/day), there may be very little cumulative

storage of fluoride (McClure et al., 1945).

Studies with radioactively labelled fluoride

suggested that the body retains about 60%

of intravenously injected fluoride (Charkes et

al., 1978; World Health Organization, 1984).

The half-life for uptake by bone tissue is very

short, about 13 minutes; both blood and

extracellular fluid levels decrease rapidly.

Approximately 99% of fluoride in the body is

found in the skeleton. The remaining portion

is distributed between the blood and soft

tissues (World Health Organization, 1984;

Thiessen, 1988).

Fluoride in human serum exists in both ionic

and nonionic forms (Taves, 1968a, 1968b;

World Health Organization, 1984). At least

half of the fluoride in the human body

consists of organic fluoride (perfluorinated

fatty acid derivatives containing 6–8 carbon

atoms) and non-ionizable fluoride from F- or

hydrogen fluoride (Ophaug and Singer,

1977; Morris and Smith, 1983; World Health

Organization, 1984; Thiessen, 1988). Guy

et al. (1976) indicated that human serum

contains much smaller quantities of

uncharacterized organic fluorocarbons. The

amount of non-ionic fluoride is related to the

total fluoride intake or uptake (Ophaug and

Singer, 1977; Morris and Smith, 1983; World

Health Organization, 1984; Thiessen, 1988).

However, if the fluoride intake or uptake is

high, the ionic form may predominate (World

Health Organization, 1984). For the general

population at a steady-state exposure to
Science Assessment Document for HF 53 CEPA/FPAC WGAQOG July 1996

fluoride, the plasma concentration of

inorganic (ionic) fluoride is directly related to

the inorganic fluoride concentration of

drinking water (World Health Organization,

1984). On the basis of the general

pharmacological behaviour of fluorides, this

relationship also holds for the uptake of

gaseous fluorides.

In a group of rural Chinese, organic fluoride

was found to contribute about 17% to serum

fluoride (Belisle, 1981). The half-life of

fluoride in plasma ranged from two to nine

hours, depending on the dose level (Guy

et al., 1976; Ekstrand et al., 1978; Singer

and Ophaug, 1979; World Health

Organization, 1984). For the same intake,

plasma fluoride/ ion concentration increases

significantly with age (Carlson et al., 1960a;

Singer and Ophaug, 1979; World Health

Organization, 1984). This might be explained

by a faster uptake by younger bone tissue,

which is less saturated with fluoride

(Weatherell, 1966; World Health

Organization, 1984). In addition, because of

the accumulation of fluoride in the skeleton,

increased amounts may be released by the

bone remodelling process into the plasma of

older individuals (World Health Organization,

1984).

The study of the distribution of fluoride from

inhaled gaseous fluorides, including

hydrogen fluoride, is complicated by fluoride

taken up orally by drinking water or food and

by absorption through skin. Animal studies

with labelled gaseous fluorides would be the

ideal source of information on the

pharmacokinetics of gaseous fluorides

(see section 6.1).

7.1.2.1 Bone

Fluoride ions are taken up by bone through

replacement of hydroxyl ions in bone apatite.

The precise mechanism of fluoride

incorporation into bone is not completely

clear (Drury et al., 1980; Rioufol et al., 1983;

World Health Organization, 1984). The

general conclusion is that absorbed fluoride

is incorporated into hard tissues primarily by

an exchange process and by incorporation

into the apatite during bone mineralization

(Thiessen, 1988). It has been suggested that

fluoride in extracellular fluid enters the

apatite crystal by a three-stage ion exchange

process. Hydroxyapatite of bone mineral

exists as extremely small crystals surrounded

by a hydration shell. Fluoride first enters the

hydration shell, in which the ions are in

equilibrium with those of the surrounding

tissue fluids and those of the apatite crystal

surface. The second-stage reaction consists

of an exchange between fluoride from the

hydration shell and the hydroxyl group at the

crystal surface. Once it has entered the

surface of the crystal, fluoride is more firmly

bound. In the third stage, some of the

fluoride may migrate deeper into the crystal

as a result of recrystallization (World Health

Organization, 1984).

The amount of fluoride present in bone

depends on a number of factors, including

fluoride intake, age, sex, bone type and the

topography of the bone. About half of

absorbed fluoride is deposited in the

skeleton, where it has a long half-life. The

concentration of fluoride in bone increases

with age (Jackson and Weidmann, 1958;

Smith et al., 1982; World Health

Organization, 1984). Fluoride can be

released from bone, as is evidenced by its

appearance in the urine in increasing

amounts after exposure has ceased or

decreased (Largent et al., 1952; Grandjean

et al., 1983; World Health Organization,

1984). Hodge and Smith (1970) suggested,

on the basis of published data, that such
Science Assessment Document for HF 54 CEPA/FPAC WGAQOG July 1996

removal of fluoride takes place in two phases

— a rapid process taking weeks and

probably involving ion exchange in the

hydration shell, and a slower phase with an

average half-life of about eight years owing

to osteoclastic resorption of bone. Human

data suggest that 2–8% of absorbed fluoride

is excreted during 18 days following the

initial retention (Spencer et al., 1975, 1981).

Because of a slower remodelling process,

fluoride is released more slowly from

compact bone such as iliac crest than from

trabecular bone (Baud et al., 1978; World

Health Organization, 1984).

7.1.2.2 Teeth

The factors controlling the incorporation of

fluoride into dental structure have been

reviewed by Weidmann and Weatherell

(1970), who concluded that the situation is

essentially the same as that pertaining to

bone (World Health Organization, 1984).

Cementum is more similar to bone than are

enamel and dentine, but its fluoride

concentration has been found to be higher

than that of bone (Singer and Armstrong,

1962). However, unlike bone, which can

continue to take up fluoride throughout an

individual's lifetime, teeth incorporate fluoride

only during the period of calcification, which

is up to about age 12 in humans (Drury et al.,

1980). Once formed, enamel and dentin

differ from bone in that they do not undergo

continuous remodelling. Fluoride

concentrations in these tissues also vary with

site, age and surface attrition, and they

increase with systemic and topical exposure

to fluoride (Weatherell et al., 1977;

Schamschula et al., 1982; World Health

Organization, 1984). In adults, fluoride

concentrations measured in the surface layer

of enamel range from 900 to 2,700 mg kg-1

(Berndt and Stearns, 1979; World Health

Organization, 1984). The average

concentration of fluoride in dentine is 2–3

times that in enamel and is affected by

growth and mineralization. As with bone and

enamel, dentin fluoride concentrations are

higher in the surface regions than in the

interior (U.S. National Academy of Sciences,

1971; World Health Organization, 1984).

7.1.2.3 Soft Tissues

The concentrations of fluoride in human soft

tissues reported by different authors vary

greatly (World Health Organization, 1984). In

general, however, only very small amounts

of fluoride are found in the normal soft

tissues. The highest levels are seen in the

kidneys (Hodge and Smith, 1965; U.S.

Environmental Protection Agency, 1980;

Heifetz and Horowitz, 1986; Thiessen, 1988).

Fluoride has a relatively short biological halflife in these organs, and the soft tissue

fluoride concentration is therefore practically

in equilibrium with that in the plasma. Unlike

fluoride in bone, the concentration does not

increase with age or duration of exposure

(Underwood, 1971; Drury et al., 1980;

Thiessen, 1980; World Health Organization,

1984).

7.1.2.4 Transplacental Transfer

Fluoride crosses the placenta. A study by

Armstrong et al. (1970) measured fluoride

from maternal uterine vessels and the

umbilical vein and artery at caesarean

section in human patients. The authors did

not find any significant gradient between

maternal and foetal blood levels, indicating

that there is no placental barrier for fluoride.

At higher fluoride levels, a partial barrier may

exist (Gedalia, 1970). The fluoride content of

the foetal skeleton and teeth increases with

the age of the foetus and with the fluoride
Science Assessment Document for HF 55 CEPA/FPAC WGAQOG July 1996

concentration in the mother (Gedalia, 1970;

World Health Organization, 1984).

7.1.3 Excretion

The principal route of fluoride excretion is via

the urine. Some excretion takes place

through sweat and faeces, and fluoride also

appears in saliva. Fluoride crosses the

placenta, but it rarely seems to be excreted

in milk to any extent (World Health

Organization, 1984).

7.1.3.1 Urine

Approximately half of absorbed fluoride is

excreted in urine (Drury et al., 1980; World

Health Organization, 1984). Urinary excretion

is the major route of fluoride clearance from

the blood and from the body. Fluoride

clearance is less than that of creatinine

(approximately 0.15 L kg-1 body weight per

hour; Ekstrand et al., 1977b). Fluoride

appears rapidly in the urine after absorption.

Intravenously injected fluoride is excreted

even more rapidly (Ekstrand et al., 1977b:

Charkes et al., 1978; World Health

Organization, 1984). Renal fluoride ion

excretion involves glomerular filtration

followed by pH-dependent tubular

reabsorption. Reabsorption occurs by nonionic diffusion of hydrogen fluoride (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) (Reynolds et al., 1978;

Whitford et al., 1979). Several factors may

influence the urinary excretion of fluoride,

such as total current exposure, previous

exposure, age, urinary flow, urine pH and

kidney status (Whitford et al., 1976; Ekstrand

et al., 1978, 1982; Schiffl and Binswanger,

1980; World Health Organization, 1984).

Urinary excretion of fluoride is decreased in

cases of renal failure or dysfunction, and

retention (i.e., bone deposition) of fluoride

increases accordingly (Gerster et al., 1983;

Kono et al., 1984a, 1984b). People with

renal dysfunction are therefore at a higher

risk for adverse health effects due to

fluoride. Some of the fluoride excreted

originates from fluoride released during bone
Science Assessment Document for HF 56 CEPA/FPAC WGAQOG July 1996

remodelling. Thus, excretion rates may

increase slightly with age, but no sex

difference in fluoride excretion has been

found (Toth and Sugar, 1976; Van de Putte

et al., 1977; World Health Organization,

1984). Younger persons who are actively

forming bone minerals excrete less fluoride

(i.e., a lower proportion of the absorbed

dose) than do adults. In situations in which

humans attain extremely high plasma levels

of fluoride, acute kidney dysfunction may

ensue, with decreased clearance of fluoride

(World Health Organization, 1984).

7.1.3.2 Faeces

Some fluoride is also excreted in the faeces.

Fluoride in the faeces is primarily ingested

fluoride that was not absorbed, and fluoride

excreted into the gastrointestinal tract does

not appear to be a major source of faecal

fluoride (Machle and Largent, 1943). This

implies that the concentration of fluoride in

the faeces will be low after dermal or

inhalation exposure to fluoride. The

proportion of the ingested fluoride that is

eliminated in the faeces varies depending on

circumstances (U.S. Environmental

Protection Agency, 1980; Maheswari et al.,

1981; Spencer et al., 1981; World Health

Organization, 1984). In persons not

occupationally exposed to fluoride and not

using fluoridated water, the faecal

elimination of fluoride is usually less than 0.2

mg/day (U.S. National Academy of Sciences,

1971). That some fluoride can be excreted

into the gastrointestinal tract is suggested by

the findings of Largent (1961), who found

that the faecal fluoride content of human

volunteers increased (2.5- to 6.7-fold,

highest amount was 0.70 mg/day) during a

period

(2–4 weeks) of hydrogen fluoride inhalation

-3, or 0.9–8.1 ppm). The

average individual exposures were between

1.2 and 3.9 mg m-3, six hours per day. No
Science Assessment Document for HF 57 CEPA/FPAC WGAQOG July 1996

coincident increase in oral fluoride (food or

water) was noted that might have accounted

for the observations.

7.1.3.3 Other Excreta

Usually, only a few percent of the fluoride

taken up is excreted in perspiration.

However, under conditions of excessive

sweating, as much as 50% of the total

fluoride excreted may be lost via this route.

These conditions can occur in cases of very

active persons or in people in hot climates

and whose water intake is therefore very

high (Crosby and Shepherd, 1957; World

Health Organization, 1984; Thiessen, 1988).

After five young men ingested 4.0–5.0 mg of

fluoride per day, the fluoride concentration in

their sweat was 0.3–1.8 mg L-1 ; two weeks

after cessation of the exposure, the

concentration was 0.2–0.3 mg L-1 (McClure

et al., 1945).

Less than 1% of absorbed fluoride is

reported to appear in saliva (Carlson et al.,

1960a; Ericsson, 1969; World Health

Organization, 1984). Salivary fluoride

concentrations are proportional to plasma

fluoride concentrations and were found to be

about 65% of plasma levels (Ekstrand et al.,

1977a; World Health Organization, 1984;

Thiessen, 1988). In fact, saliva does not

represent pure excretion, because most of

the fluoride will be recycled in the body.

However, the fluoride content of the saliva is

of major importance for maintenance of

fluoride levels in the oral cavity (World Health

Organization, 1984).

The concentration of fluoride in human milk

is quite similar to that in plasma (Ekstrand

et al., 1981), and significant exposure to

fluoride through human milk is therefore very

unlikely (World Health Organization, 1984).

Observed fluoride levels in human milk are

between 2 and 8 μg L-1, less than those in

most milk substitutes (Thiessen, 1988).

7.1.4 Monitoring Exposure to Gaseous

Fluoride by Pharmacokinetic Parameters

Kono et al. (1987) measured urinary fluoride

concentrations pre-shift and post-shift in 142

workers exposed to hydrogen fluoride in their

workplace at a level of 3 ppm (2.5 mg m-3)

and in 80 unexposed workers (ages 18–59).

They reported a linear relationship between

the mean urinary fluoride concentrations and

the hydrogen fluoride concentration in the

air. The mean urinary fluoride value was

4 mg kg-1 for exposed workers.

Pre- and post-shift serum and urine samples

of 142 hydrogen fluoride workers were

compared with those of 270 unexposed

workers (Kono et al., 1992). The preexposure levels of serum and urinary fluoride

in hydrogen fluoride workers were found to

be higher than the control values, suggesting

that fluoride excretion from the body did not

return to control levels in the inter-shift period

(12 hours). The post-shift serum and urinary

fluoride concentrations of hydrogen fluoride

workers were significantly higher than the

pre-shift concentrations. A good correlation

was obtained between serum fluoride and

urinary fluoride concentrations. There was a

linear relationship between mean serum

fluoride concentration and hydrogen fluoride

concentration in the workplace. A mean

serum fluoride concentration of 82.3 μg L-1

was estimated to correspond to an

atmospheric hydrogen fluoride concentration

of 3 ppm (2.5 mg m-3). This is the maximum

allowable environmental concentration

recommended by the Japanese Association

of Industrial Health (1964) and by the
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American Conference of Governmental

Industrial Hygienists (1967).

In a similar study, Kono et al. (1993)

recorded hair, urine, and serum fluoride

concentrations pre- and post-shift in workers

exposed to hydrogen fluoride in the

workplace. This study confirmed the linear

relationship between serum and urinary

fluoride concentrations and the hydrogen

fluoride concentration in the workplace. The

results support the speculation that fluoride

is excreted in the hair after long-term

exposure to hydrogen fluoride. The studies

of Kono et al. (1987, 1992, 1993) suggest

that actual exposure to hydrogen fluoride

can be monitored by determining the serum,

urinary and hair fluoride concentrations.

Ehrnebo and Ekstrand (1986) monitored

individual plasma and urine fluoride

concentrations pre- and post-shift in workers

at an aluminum plant in Sweden. They

concluded that when fluoride exposure and

body burden are to be studied on an

individual basis, the area under the plasma

concentration–time curve and the amount of

fluoride excreted give better quantitative

information than urinary fluoride

concentration measurements.

7.2 PHARMACODYNAMICS

Fluoride toxicity involves at least four

categories of major functional derangements

(Hodge, 1969; Gosselin et al., 1984;

Thiessen, 1988): (1) inhibition of enzymes

controlling glycolysis or other vital pathways;

(2) hypocalcaemia, 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 also has

effects on inorganic phosphate and

potassium concentrations in serum

(Boink, 1993).

The literature on the influence of fluoride on

enzyme systems is extensive. Both activating

and inhibiting effects on enzymes have been

described. Fluoride (as F- or as

undissociated hydrogen fluoride) may exert a

direct action on the enzyme itself. More

frequently, however, the effect is indirect,

involving complexation with a metal (e.g.,

Ca2+ or Mg2+) associated with the enzyme

(Edwards et al., 1984; World Health

Organization, 1984; Anonymous, 1985;

Thiessen, 1988).

Reviews of the literature (Hodge and Smith,

1965; Taves, 1970; Wiseman, 1970; Drury

et al., 1980; Swedish Fluoride Commission,

1981) suggest that low concentrations (about

10 μmol/L, i.e., 0.18 mg L-1) of fluoride in

serum (but still much higher than normal) will

stabilize and activate several soluble and

membrane-bound enzyme systems,

including adenyl cyclase (World Health

Organization, 1984). Alkaline phosphatase

activity may be increased by fluoride (Farley

et al., 1983), but changes in serum activity

levels of this enzyme, and in serum calcium

and phosphate, have been found to be

minimal in potroom workers with skeletal

fluorosis (Boillat et al., 1979).

At higher serum fluoride concentrations

(at least 0.3 mg L-1), fluoride will inhibit many

enzymes (World Health Organization, 1984).

Pyrophosphatase, for instance, is inhibited

by about 50% at 0.4 mg L-1, a level that is

higher than that found in the plasma of an

individual with a skeletal fluoride content of

6,000 mg kg-1 and exposure to fluoride levels

of 19 mg L-1 in drinking water (Ericsson et al.,

1973). In rats, fluoride ion has been shown

to be a potent inhibitor of liver cytosolic
Science Assessment Document for HF 59 CEPA/FPAC WGAQOG July 1996

pyrophosphatase (Baykov et al., 1992), the

equilibrium inhibition constant for this

enzyme being an order of magnitude lower

than that for enolase. Baykov et al. (1992)

suggested that fluoride-induced inhibition of

pyrophosphatase may lead to an increase

in cellular pyrophosphatase, which in turn

inhibits fatty acid oxidation, protein and

nucleic acid synthesis and bone formation

and growth.

Among the results of enzyme inhibition by

fluoride are hyperkalaemia and metabolic

acidosis (Gosselin et al., 1984; World Health

Organization, 1984). In acute fluoride

poisoning, inhibition of metalloenzymes

involved in essential processes can cause

vital functions such as the initiation and

transmission of nerve impulses to cease.

Fluoride has been shown to affect the

metabolism of glucose, lipids, 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 (Watanabe et al., 1975; Aitbaev,

1984; Dousset et al., 1984; Drozdz et al.,

1981, 1984; Den Besten, 1986; Thiessen

et al., 1988; Boink, 1993). In these cases,

serum fluoride levels, when reported, were at

least 50 μg L-1 (Thiessen et al., 1988).

Studies in humans have shown minimal

increases in urinary cyclic adenosine

monophosphate excretion and unchanged

plasma levels following an oral intake of

about 7 mg fluoride, which resulted in peak

plasma fluoride levels of about 0.3 mg L-1

(Mornstad and Van Dijken, 1982).

In the mineralization of bones and teeth, the

proteoglycans and their constituent

glycosaminoglycans form an integral part of

the organic matrix of these tissues. Fluorideinduced changes in the formation of these

compounds could be part of a common

mechanism for the skeletal and dental

effects of fluoride. Studies on rats have

shown that the proteoglycans undergo

molecular changes, particularly in terms of

decreased size, during the development of

dental fluorosis (Smalley and Embery, 1980).

In rabbits, glycosaminoglycans show major

changes, with the novel appearance of

dermatan sulphate, an

iduroglycosaminoglycan in fluorotic bone

(Jha and Susheela, 1982a, 1982b). The

serum of patients with endemic fluorosis

(both skeletal and dental) contains

decreased concentrations of sialic acid and

increased levels of glycosaminoglycans

compared with controls. Parallel results have

been reported for rabbits dosed with sodium

fluoride at 10 mg kg-1 body weight daily for

eight months (Jha et al., 1983).

The strong affinity of fluoride for calcium

results in hypocalcaemia. Fluoride

intoxication following dermal exposure to

hydrogen fluoride solutions or ingestion of

fluoride salts is characterized by severe

hypocalcaemia. Total calcium concentrations

as low as 1 mmol/L (normal 2.2–2.6 mmol/L)

have been found in the plasma of patients

intoxicated with fluoride, whereas total

protein, which binds approximately half of

the calcium present in plasma, was normal

(Boink, 1993). This fluoride-induced

hypocalcaemia was accompanied by a rise in

plasma parathyroid hormone, indicating that

the normal physiological response to

hypocalcaemia of the parathyroid gland is

not affected by fluoride in humans or in

animals (Simpson et al., 1980; Kono et al.,

1982; Boink, 1993). It has been postulated

that fluorapatite is responsible for the

hypocalcaemia (Simpson et al., 1980; Boink,

1993). If the formation of fluorapatite is

involved in the aetiology of hypocalcaemia,
Science Assessment Document for HF 60 CEPA/FPAC WGAQOG July 1996

its structural formula [3Ca3(PO4)2 CaF2]

suggests that the inorganic phosphate

concentration in plasma will decrease during

fluoride intoxication (Boink, 1993). This is

indeed the case (Handler, 1945; Boink,

1993). Changes in serum inorganic

phosphate concentrations are the result of a

combination of (1) phosphate release from

cells, (2) calcium mobilization from bone

matrix, compensating for hypocalcaemia,

during which process phosphate ions are

released, (3) formation of fluorapatite, during

which process phosphate ions are bound,

and (4) impaired renal tubular phosphate

metabolism (Boink, 1993). After

intraperitoneal administration of sublethal

doses of fluoride in rats, increased urinary

phosphate excretion is observed (Kessabi

et al., 1980).

Hypocalcaemia in cases of acute fluoride

poisoning will often result in severe

involuntary muscle contractions (tetany)

(Gosselin et al., 1984). Many of the other

effects of fluoride, including cardiac

arrhythmias and other effects often

associated with acute systemic fluoride

poisoning, are thought to be caused by

hypocalcaemia (Abkurah et al., 1972;

Tepperman, 1980; Kono et al., 1982;

Gosselin et al., 1984; Heifetz and Horowitz,

1986; Thiessen, 1988).

Fluoride-induced potassium leakage from

erythrocytes has an absolute requirement for

the presence of extracellular calcium (Lepke

and Passow, 1968). McIvor and Cummings

(1987) suggested that fluoride causes

potassium leakage from erythrocytes by

inhibiting Na+,K+-ATPase, which in turn leads

to a rise in intracellular sodium concentration

and subsequent Na+–Ca2+ exchange. In two

fatal cases of fluoride intoxication of humans

(Baltazar et al., 1980; McIvor et al., 1983)

and in experimental fluoride intoxication in

dogs, rats and pigs, hyperkalaemia has been

observed (Baltazar et al., 1980; Boink,

1993). Hyperkalaemia can result in

ventricular fibrillation of the heart associated

with
Science Assessment Document for HF 61 CEPA/FPAC WGAQOG July 1996

peaking of the T-waves in the

electrocardiogram (Baltazar et al., 1980).

Hypokalaemia has also been reported in one

human case study (Abkurah et al., 1972).

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 that are involved result from a

combination of factors such as fluid and

electrolyte losses (due to vomiting and

diarrhoea or intragastric bleeding) and

central vasomotor depression. Brain damage

from acute fluoride poisoning can cause

such symptoms as convulsions, lethargy,

stupor and coma. 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, although it is probably not a major

concern in cases of chronic fluoride

exposure. Note that renal failure does not

appear to be a cause of death in fluoride

poisonings (Gosselin et al., 1984). More

severe nephrotoxicity, also including

diabetes insipidus, may occur from exposure

to fluorine-containing anaesthetic agents

such as methoxyflurane or enflurane (World

Health Organization, 1984; Thiessen, 1988).

Because of the chemical similarities between

the halogens iodine and fluorine, there has

been much interest in the possible effects of

fluoride on the thyroid (e.g., formation of

goitre) (Day and Powell-Jackson, 1972;

World Health Organization, 1984). Other

investigations have failed to reveal any

evidence that fluoride is responsible for any

disorder of the thyroid (Demole, 1970; Royal

College of Physicians, 1976; Sonneborn and

Mandelkow, 1981).

7.3 EFFECTS IN HUMANS

A number of case reports on acute or chronic

poisoning by inhalation or exposure of skin

to airborne hydrogen fluoride have been

published, some of which have already been

reviewed by Heitman (1976), the World

Health Organization (1984) and Thiessen

(1988). Very little information from clinical

studies is available on other gaseous

fluorides. Most of the clinical cases of

poisoning by hydrogen fluoride or other

fluorides do not provide accurate quantitative

data; at best, they provide some indication of

the exposure levels leading to symptoms of

toxicity.

Most case studies of acute or chronic

intoxication by inhalation of hydrogen

fluoride or skin exposure concern accidents

in the work environment, whereas acute

intoxication with liquid hydrogen fluoride or

fluoride salts was associated with suicidal or

accidental ingestion of fluoride-containing

products used in the home (World Health

Organization, 1984).

Gaseous fluoride compounds attack tissues

much more vigorously than fluoride salts.

The toxicity of some gaseous inorganic

fluoride compounds decreases in the

following order: F2O, F2, HF, BF3 and H2SiF6

(World Health Organization, 1984).

The odour threshold for hydrogen fluoride is

reported to range from 0.02 to 0.22 mg m-3

(0.02–0.27 ppm) (Sadilova, 1967; Lindberg,

1968).
Science Assessment Document for HF 62 CEPA/FPAC WGAQOG July 1996

7.3.1 Acute and Short-term Health

Effects

In general, practically all the organs and

systems are affected in acute fluoride

poisoning after oral exposure to hydrogen

fluoride or fluorides. The manifestations

include vomiting (sometimes blood-stained),

diffuse abdominal pain of spasmodic type,

diarrhoea, cyanosis, severe weakness,

dyspnoea, muscle spasm, pareses and

paralyses, cardiovascular disorders,

convulsions and coma (Hodge and Smith,

1965; World Health Organization, 1984;

Thiessen, 1988). Although much has been

reported on acute poisoning by hydrogen

fluoride and other fluorides, the exact cause

of death is not yet known (Boink, 1993).

Massive impairment of the functioning of vital

organs results in cell damage and necrosis.

Terminally, there is a characteristic shocklike syndrome (World Health Organization,

1984).

Gaseous fluorides can trigger a local

reaction, causing considerable damage to

the skin, eyes and respiratory tract (World

Health Organization, 1984). Hydrogen

fluoride vapour was reported to also cause

skin burn (Browne, 1974; Largent, 1961). At

a concentration averaging 2.1–4.7 mg m-3

(2.6–5.7 ppm), hydrogen fluoride was

reported to cause very slight irritation of the

face and eyes; frequent cutaneous erythema

was noticed; in one case, flaking of the

epithelium, resembling sunburn, was seen.

Machle et al. (1934) reported the effects of

airborne hydrogen fluoride on two human

subjects. The highest concentration that the

subjects were able to tolerate for more than

one minute was 100 mg m-3. At this level,

there was smarting of the exposed skin in

less than one minute, and conjunctival and

respiratory irritation was marked. At

50 mg m-3 (61 ppm), the same effects were

noticed with the exception of the skin

irritation, but tickling and discomfort in the

larger air passages were noticeable with

each inspiration. At 26 mg m-3 (32 ppm), eye

and nose irritation was mild and could be

tolerated for several minutes. There was no

coughing or sneezing. The taste of hydrogen

fluoride was reported at all three

concentrations.

Largent (1952) listed the increasing intensity

of acute effects of increasing concentrations

of gaseous fluorides on the basis of

controlled exposures of volunteers as

follows: 2.1 mg m-3 (3 ppm) caused no local

immediate effects; 7 mg m-3 (10 ppm)

caused discomfort in many subjects; 21 mg

m

-3 (30 ppm) revealed complaints in all

subjects and made them object to staying in

the test environment; brief exposure to 42

mg m-3 (60 ppm) caused definite irritation of

the conjunctiva and nasal passages and

tickling and discomfort of the pharynx and

trachea; and 84 mg m-3 (120 ppm), the

highest concentration tolerated (less than

one minute by two male subjects), resulted in

the previously mentioned effects and

smarting of the skin. Thus, the NOAEL in this

experiment for local effects was 2.1 mg F- m3

.

Elkins (1959) reported complaints of

nosebleeds in workers engaged in the

hydrogen fluoride etching process and in one

plant where welders were exposed to

fluoride at 0.4–0.7 mg m-3.

In an experimental inhalation study with

hydrogen fluoride, five human volunteers

were exposed six hours per day, five days

per week, for 10–50 days, at average

concentrations of 1.42–4.74 ppm hydrogen

fluoride (1.16–3.89 mg m-3). Slight irritation of

the nose was noticed in all subjects at
Science Assessment Document for HF 63 CEPA/FPAC WGAQOG July 1996

concentrations averaging 2.59–4.74 ppm

hydrogen fluoride (2.12–3.89 mg m-3),

ranging from 1.8–7.9 ppm (1.5–6.5 mg m-3).

No signs or symptoms of liver toxicity or

respiratory tract irritation were reported at

these average concentrations (Largent,

1961). The NOAEL for skin and eye irritation

in this study was 0.9 mg m-3 (1.1 ppm). A

NOAEL for systemic effects could not be

established.

Pulmonary exposure to gaseous hydrogen

fluoride may occur independently of or

simultaneously with skin exposure.

Continued inhalation of hydrogen fluoride

results in coughing, choking and chills,

lasting 1–2 hours after exposure. In the next

one or two days, fever, coughing, chest

tightness, rales and cyanosis may develop,

indicating delayed pulmonary oedema

(Dreisbach, 1971). The signs and symptoms

progress for a day or two and then regress

slowly over a period of a few weeks. At

higher exposures to gaseous hydrogen

fluoride, the delicate tissues of the lung may

be intensely and even fatally irritated.

A report by Gaugl and Wooldridge (1983)

suggested that pulmonary damage due to

inhibition of surfactant synthesis may result

from systemic fluoride poisoning, even if the

fluoride was not inhaled. Death from acute

fluoride poisoning, whether from hydrogen

fluoride inhalation or burns from ingestion of

fluoride salts, is usually from cardiac or

respiratory failure and generally occurs within

24 hours (Heifetz and Horowitz, 1986;

Thiessen, 1988).

As a result of an accident with the

convection section of a hydrogen fluoride

alkylating heater of an oil refinery, an

estimated 24,000 kg of caustic hydrogen

fluoride were released from a storage tanker.

In total, 939 persons who were potentially

exposed to airborne hydrogen fluoride were

examined for symptoms of intoxication, and

their emergency room and hospital records

were studied. Most persons present at the

emergency room were female (56%) or

black (60%), and their mean age was 33.9

years. The most frequently reported

symptoms were eye irritation (41.5%),

burning throat (21%), headache (20.6%) and

shortness of breath (19.4%). Physical

examination results were normal for 49% of

the cases. Decreased pulmonary function

was demonstrated by a pulmonary function

test (42.3% < 80% of the predicted value for

forced expiratory volume in the first second

[FEV1]). Hypoxaemia (<80 mm Hg in 17.4%)

and hypocalcaemia (<8.5 mg dL-1 in 16.3%)

were also noted. Ninety-four individuals were

hospitalized, with an average stay of

approximately two days, and more than 83%

of all cases were discharged with a primary

diagnosis of "hydrogen fluoride exposure."

There were no fatalities. The ambient air

concentration of hydrogen fluoride was not

monitored (Vernon et al., 1991; Wing et al.,

1991). Neither an effect level nor a NOAEL

could be established.

Serum fluoride concentrations of 3–

15.5 mg L-1 have been associated with fatal

cases of fluoride poisoning, from oral

ingestion of fluorides, skin burns and

inhalation of hydrogen fluoride (Greendyke

and Hodge, 1964; Hodge and Smith, 1965;

Yolken et al., 1976; Tepperman, 1980;

Gosselin et al., 1984). One case was

reported in which the serum fluoride level at

autopsy was only 67 μg L-1 (Burke et al.,

1973), although one victim of oral fluoride

(NA2SiF6) poisoning survived despite a

serum fluoride concentration of 14 mg L-1 six

hours after ingestion (Yolken et al., 1976).
Science Assessment Document for HF 64 CEPA/FPAC WGAQOG July 1996

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-1 (3.5 hours after

the poisoning accidents) have been reported

(Burke et al., 1973; Yolken et al., 1976).

Fluoride concentration also increased in soft

tissues following fatal intoxication. Levels of

10.6 mg kg-1, 4.6–11.6 mg kg-1, 4.4–

11.2 mg kg-1 and 12.4–15.6 mg kg-1 have

been reported in heart, kidney, liver and lung

tissue, respectively, following fatal intake of

sodium fluoride (Hodge and Smith, 1965).

7.3.2 Chronic Health Effects

The clinical and epidemiological studies

described in this section have been

organized according to the predominant type

of effect investigated or observed in each

study.

7.3.2.1 Effects on the Respiratory System

Leidel et al. (1967) studied the effects of

chemical irritations on exposed workers

(305) in a chemical plant where hydrogen

fluoride was only one of the primary

chemicals produced. The control group

consisted of 88 workers in a box plant.

Twenty-eight samples of airborne hydrogen

fluoride were taken, with sampling periods

ranging from 10 to 30 minutes. The

concentration of hydrogen fluoride ranged

from 0.07 to 10.0 ppm (0.06–8.2 mg m-3),

with a mean of 1.03 ppm (0.85 mg m-3). The

samples for particulate fluoride were all

under 0.5 mg m-3 (0.1–0.49 mg m-3). The

mean age of the chemical plant workers was

44 years, 14 years older than that of the box

plant workers. The observed values for

forced vital capacity (FVC), one-second

forced expiratory volume (FEV1) and

FEV1/FVC for the total group were within

about 3% of the predicted normal values,

with no significant difference between the

chemical workers and the control group. The

residual volume expressed as 5% of total

lung volume was 30.8% in the chemical

workers and 26.8% in the box plant workers,

with both values within normal limits (35%,

upper limit). This difference could be

explained by the difference in average age

of the two groups. If a correction were made

for age and smoking, no effect of workrelated exposure would be established. The

urinary fluoride concentration before the shift

in the exposed group ranged from 0.33 to

0.48 mg L-1, compared with 0.95–26.6 mg L-1

after the shift. For the control group, these

ranges were 0.50–1.88 and 0.50–2.38 mg L1

, respectively.

In a plant for the electrolytic extraction of

aluminum, which began operating in 1973,

207 workers were medically examined in

view of some complaints of respiratory

symptoms, which they associated with

occupational exposure. The exposures

measured at different working places ranged

between 0.27 (0.32 ppm) and 4.1 mg m-3

(5.0 ppm) for hydrogen fluoride, between

0.02 and 1.6 mg m-3 for particulate fluorides

and between 0.08 and 4.0 mg m-3 for sulphur

dioxide. The exposure levels were

occasionally higher than the threshold limit

values in Yugoslavia (1.7 mg m-3 [2.1 ppm]

for hydrogen fluoride; 1 mg m-3 for fluoride

expressed as F; and 10 mg m-3 for sulphur

dioxide). The results of the study showed

that only 4.9% of workers had symptoms

defined as chronic bronchitis (87% of

workers were <40 years of age). On the

other hand, a rather large number (10.2%)

complained of paroxysmal wheezing with

dyspnoea. Out of 21 subjects with such

complaints, 19 claimed that the bronchoconstrictive symptoms appeared after they
Science Assessment Document for HF 65 CEPA/FPAC WGAQOG July 1996

had started to work in the potrooms. Only

two of them had similar symptoms earlier.

Pulmonary function tests revealed a slight

decrease in the mean values (compared with

the predicted values) of FVC and FEV1 and

a higher decrease in the mean values of

mean expiratory flow, particularly in those

workers who complained of paroxysmal

wheezing with dyspnoea. Owing to the

technological process used in the plant, it is

most likely that the respiratory effect is due

to the action of hydrogen fluoride (and

particulate fluoride). However, the

mechanism of increased respiratory

susceptibility remains to be clarified (Saric

et al., 1979). The design of the study did not

permit an exact identification of the toxic

cause or the establishment of a NOAEL.

A group of 74 workers in a hydrogen fluoride

plant who had been exposed to hydrogen

fluoride (periodically severely) for an average

of 2.7 years was studied. On a few

occasions, there had been cases of upper

respiratory tract irritation. Repeated chest

X-rays over a five-year period did not reveal

any visible evidence of lung changes and did

not differ from those of unexposed workers.

Periodic clinical examinations did not reveal

any incidence of pulmonary infection in the

exposed workers (Evans, 1940).

Johnson et al. (1973) conducted a study of

an aluminum reduction facility for the primary

purpose of collecting and analysing airborne

dust, coal tar, pitch volatiles, fluorides,

carbon monoxide and sulphur dioxide.

Although obstructive airway changes had

developed in some workers, the investigators

concluded that it was not justified to link the

changes to a particular exposure because of

the many contaminants involved in the

potroom area.

A study was carried out on 1,242 aluminum

smelter workers to assess the impact on the

lungs of exposure to multiple pulmonary

irritants, including gaseous and particulate

fluoride and sulphur dioxide. A pulmonary

risk index was generated for each worker

which accounted for the nature, intensity,

duration and multiplicity of exposure. History

and symptoms of pulmonary disease,

spirometry and chest X-rays were performed

on all 1,242 individuals, whereas singlebreath diffusing capacity was tested in 460.

The results were then compared in those at

low, moderate and high pulmonary risk.

Highly significant differences were observed

between those with abnormal FEV1s and

FEFs and a high pulmonary risk index.

Twenty-nine percent of all the workers and

10% of the 460 in whom the diffusing

capacities were tested were also found to

be abnormal (Carnow and Conibear, 1978).

No exposure levels were indicated, and no

association could be drawn between the

results and exposure to hydrogen fluoride

alone (only an abstract was available).

Ernst et al. (1986) explored the relationship

between respiratory symptoms and lung

function and exposure to ambient air

pollution consisting of particulate and

gaseous fluorides. The subjects were 253

North American Indian children 11–17 years

of age living on the Akwasasne reserve,

which is adjacent to an aluminum smelter.

Among boys, closing volume was increased

in those raised closest to the smelter

compared with those having lived most of

their lives farthest from this source of air

pollution. The ambient hydrogen fluoride

concentration in the air was not reported. In

both sexes, there was a significant linear

relationship between increasing CV/VC%

and the amount of fluoride contained in a

spot urine sample. The authors concluded
Science Assessment Document for HF 66 CEPA/FPAC WGAQOG July 1996

that exposure to fluoride air pollution in the

community may be associated with

abnormalities in small airways. The

implication of these abnormalities for future

respiratory health is unknown. No fluoride

concentrations in urine were included in this

report.

Children living in the vicinity of a phosphate

processing facility and exposed to fluoride

concentrations ranging from about 100 to

500 μg m-3 exhibited an impairment of

respiratory function. It is noted, however, that

it is unknown whether the concentrations

were gaseous or total fluoride, and no other

pollutants were recorded (Gezondheidsraad,

1981). In another study, no effects on

respiratory function were observed at

gaseous fluoride concentrations up to

16 μg m-3 (Biersteker and Boleij, 1986).

The effects on the respiratory tract as

observed in health assessments with regard

to exposure were discussed by Wibowo and

Zielhuis (1986). Occupational exposure to

inorganic fluoride at concentrations of

500 μg m-3 (200 μg/m3 gaseous fluorides)

was concluded to cause an increase in the

incidence of irritations of the upper

respiratory tract. However, these results may

have been influenced by other air pollutants.

In another study, exposures to considerably

higher levels of gaseous hydrogen fluoride

(1,700 μg m-3, or 2,074 ppb) were reported

not to cause any appreciable effect on the

respiratory tract (Wibowo and Zielhuis,

1986).

Lung function and bronchial reactivity were

measured in 38 aluminum potroom workers

with no airway symptoms and in 20 healthy

referents (office workers). All participants

were non-smokers. The magnitude of

exposure to airborne dust (alumina) and

fluorides was determined. The mean

exposure values were 1.77 (0.49–4.5) mg m3

 for total dust and 0.31 (0.1–0.5) mg m-3 for

total (gaseous and particulate) fluorides. The

"worst-case" estimates showed mean values

for gaseous fluorides of up to 3.13 mg m-3

during work with gas skirt exchanges. The

aluminum potroom workers had obstructive

lung function impairment with a significant

decrease in expiratory flow and an increase

in residual volumes. Diffusing capacity was

found to be lower than in the controls. No

bronchial hyperreactivity was found in the

aluminum potroom workers. The exposure to

inhaled alumina and particulate and gaseous

fluorides in the plant was low, 15–20% of the

Swedish exposure limits (10 mg m-3 for

alumina and 2 mg m-3 for fluorides). The

finding of only modest lung function

alterations with no bronchial hyperreactivity

in the aluminum potroom workers is not

consistent with the results of other

investigators. This discrepancy can probably

be explained by the fact that the exposure to

inhaled contaminants in the investigated

aluminum plant was low (Larsson et al.,

1989).

Golusinski et al. (1973) examined the

mucosa in 130 aluminum plant workers

exposed to hydrogen fluoride. Monitoring of

hydrogen fluoride concentrations in the

atmosphere of electrolytic halls showed that

the concentration of hydrogen fluoride often

considerably exceeded 0.5 mg m-3 (0.6 ppm,

the Polish threshold limit value). In 30% of

these workers, chronic inflammatory

changes, either hypertrophic or atrophic

rhinitis, were observed in the nasal mucosa.

Biopsy specimens of septal mucosa were

examined histologically. In the patients with

hypertrophic rhinitis, numerous inflammatory

infiltrates, consisting of mononuclear cells,

were observed. The blood vessels were

dilated, and extravasations of erythrocytes
Science Assessment Document for HF 67 CEPA/FPAC WGAQOG July 1996

were noted. The connective tissue stroma

showed evidence of oedema and

hyperactivity of the sero-mucous glands. In

the atrophic mucosa, fibrosis and

hyalinization of connective tissue stroma

were seen associated with moderate

inflammatory infiltrates and evidence of

hypoactivity of the glands.

Burr et al. (1990) studied the health situation

of workers in a glass company as related to

exposure to noise and a number of air

pollutants, such as organic solvents and

hydrogen fluoride. The exposure to hydrogen

fluoride ranged from 0.34 to 3.0 mg m-3

(0.41–3.66 ppm). As well as the 171 workers'

complaints of occupational pneumoconiosis,

hearing loss and cumulative disorders were

also diagnosed. The authors concluded that

the workers were potentially exposed to

cumulative trauma, acid mists and noise. No

specific associations between hydrogen

fluoride exposure and toxic symptoms could

be concluded, owing to multiple exposures.

Following an accident at an oil refinery in

Texas City, Texas, which released about

40,000 pounds of hydrogen fluoride (Vernon

et al., 1991; Wing et al., 1991), a populationbased epidemiological study was conducted

to evaluate the impact of the accident on the

health of the surrounding community (Dayal

et al., 1992). Exposure assessment was

done using a multipronged approach through

a door-to-door survey of 10,811 individuals.

A symptom survey resulting in 1,994

completed interviews was conducted with a

stratified random sample selection. The

results showed a strong relationship (p < 10-

4

) between the exposure (not given in the

publication) and symptoms reported

following the accident and two years later,

most notably breathing and eye symptoms.

However, substantial improvement in health

was reported over the two-year period,

regardless of the exposure level. Although

the authors recognized that recall bias and

behavioural sensitization possibly led to an

overestimation of the effect, they concluded

that it was difficult to dismiss the

interpretation that hydrogen fluoride

exposure indeed caused health problems in

the community that continued for at least two

years after the accident. No hydrogen

fluoride or other gaseous fluoride

concentrations in ambient air were reported.

A case report describes the symptoms of a

57-year-old worker who had been working

for 10 years, eight hours a day, in the

alkylation unit of an oil company, where

volatile fluorides were possibly released to

the atmosphere during loading and

unloading and where tar residues that

liberated fluoride fumes on exposure to air

were frequently produced. The worker was

possibly exposed to variable and unknown

concentrations of hydrogen fluoride, either

from ambient air or from fumes. Episodes of

obvious acute poisoning were not

uncommon, when immediate contact with the

fumes caused symptoms and signs of

intense eye irritation, tearing, blurred vision

and marked dyspnoea with severe

respiratory tract pain and coughing. If he

could not get quickly away, the worker

developed nausea, epigastric pain, vomiting

and sudden weakness. Such apparent acute

episodes occurred approximately 10–15

times a year. The noxious and irritating

odour of hydrogen fluoride was stated to

have been identified. Within 1–2 years after

starting this work, the worker began having

rectal incontinence with diarrhoea. He

developed severe headaches, increasing

weakness upon exertion and pain in the

lower back. Leg and back pain became so

severe that medical consultation was
Science Assessment Document for HF 68 CEPA/FPAC WGAQOG July 1996

necessary after eight years. The symptoms

progressed, and intellectual dysfunction was

also diagnosed. Finally, osteoarthritis of the

spine was diagnosed, abnormalities in the

bladder were detected and lung function was

decreased considerably (Waldbott and Lee,

1978). No accurate exposure levels were

measured.

7.3.2.2 Effects on Bones and Teeth

Roentgenological examinations of the lumbar

spine of hydrogen fluoride workers showing

high urinary fluoride concentrations (4.31–

26.6 mg L-1) did not show any skeletal

fluorosis. In a follow-up study of four workers

two years later, one worker showed a slight

first-degree osteosclerosis, which was not

associated with disability. This worker had

been employed for 11 years in a hydrogen

fluoride plant (Leidel et al., 1967).

Peperkorn and Kahling (1944) performed

clinical and radiological examinations of 47

workers exposed to airborne hydrogen

fluoride, hydrofluoric acid and cryolite. No

quantitative exposure data were given.

Nearly all of the workers complained of mild

to moderate back pain and stiffness, with

pain in the cervical spine in some cases.

Some complained of pain in the thighs and

knees. The majority of the men reported

shortness of breath on exertion. There was

little evidence of cough, expectoration or

asthmatic conditions. Except for a few cases

of skin burns, physical and chemical clinical

findings were normal. Seventy-two percent of

the workers showed osteosclerotic changes

varying from first degree to third degree.

Characteristics of first-degree osteosclerosis

included increased bone density and

thickened and misshapen structure of the

trabeculae, with the marginal contours of the

bones exhibiting slight blurring. In seconddegree osteosclerosis, the findings were

more pronounced. The outer boundaries of

the bones had become more irregular,

insertions of the tendons had started to

calcify and the cortical substance of the long

bone was widened, restricting the medullary

canal. In third-degree osteosclerosis, the

bone had become radiographically opaque

and the insertions of tendons, ligaments and

interosseous membranes were calcified. The

first evidence of changes was found in the

pelvis and lumbar spine. As the process

advanced, the changes spread to the rest of

the spinal column and the ribs, with

extremities affected last. The degree of

radiological changes increased with the

duration of employment. No exposure data

were given.

A case of intoxication by long-term exposure

(15 years) to airborne hydrogen fluoride of a

40-year-old worker in a hydrogen fluoride

plant was reported by Peperkorn and Kahling

(1944). After seven years of employment,

the worker began to have "rheumatic pains,"

which, over the years, increased until he

became totally disabled. He complained of

stiffness in all joints, except hands and feet.

He had difficulty breathing when walking or

climbing. He was prematurely aged,

emaciated and pale, had a stiff posture and

walked with small steps. Chest expansion

was limited, as were movements of the

spine, hips and shoulders. Red and white

blood cell counts, sedimentation, blood

calcium and urinalysis were all reported

normal. No urinary fluoride levels were

obtained. X-rays of the skeletal system

showed third-degree osteosclerosis

(Heitman, 1976). Exposure levels of airborne

hydrogen fluoride were not determined.

A clinical study was carried out on a group of

workers exposed intermittently to hydrogen
Science Assessment Document for HF 69 CEPA/FPAC WGAQOG July 1996

fluoride and, to a lesser degree, calcium

fluoride dust in a hydrofluoric acid

manufacturing plant, during an observation

period of five years. The exposure took place

during repair, and concentrations ranged

from 11 to 21 mg F- m-3 (13–26 ppm). The

mean urinary fluoride excretion of exposed

workers was 3.65 mg L-1 (ranging from 4 to

24 mg L-1). No significant effects on chest

X-ray, haemoglobin or red and white blood

cell counts were detected. Roentgenological

examinations of the pelvis and spine of 10

men working with the greatest potential

exposure did not show skeletal fluorosis after

five years of intermittent exposure (Machle

and Evans, 1940).

Dale and McCauley (1948) provided data on

the medical and dental conditions of workers

engaged in the production of hydrofluoric

acid for 2–33 years. Eleven unexposed

office and warehouse workers served as

controls. No workplace airborne hydrogen

fluoride levels were determined, but it was

reported that window glass in a building

housing the hydrofluoric acid retorts

corroded in a few months' time and had to be

replaced periodically. Some workers in close

proximity to the retorts experienced transitory

hyperaemia of the exposed skin. The skin of

the faces and hands appeared dehydrated,

roughened and irritated in the majority of the

workers. Dental examinations showed fewer

caries and fillings in the exposed group. In

the trabecular pattern of the osseous

structure of the upper and lower jaws,

changes were seen in 24 of the 40 workers,

and questionable changes in eight. The bone

changes were characterized by an increase

in the number and thickness of trabeculae

and a corresponding decrease in the

intratrabecular and canalicular species. The

urinary fluoride excretion of 34 exposed

workers in spot samples ranged from 0.89 to

49.3 mg L-1 (with a mean of 10.8 mg L-1).

In a clinical study workers at a phosphoric

acid producing plant, hydrogen fluoride and

silicon tetrafluoride were released, but the

airborne fluoride concentration was

maintained below 3 ppm and averaged

2.4 ppm gaseous fluoride. Medical and

radiological examinations revealed no

abnormalities. No consistent urinary fluoride

excretion above 5 mg L-1 was observed

(Rye, 1961).

Derryberry et al. (1963) reported the

prevalence of osteosclerosis in 74 workers in

a fertilizer manufacturing plant in relation to

fluoride exposure. Fluorides in the form of

dust and gases in varying combinations and

concentrations were produced throughout

the process. A weighted airborne exposure

was calculated for the period of employment

of each worker. The individual exposure to

fluoride was 0.50–8.32 mg m-3, with 1.78–

7.73 mg m-3 being associated with increased

bone density observed in workers. The

difference in averages between the

increased bone density group (average

fluoride exposure 3.38 mg m-3) and the

remainder of the exposed group, which

showed significantly less bone density

(average fluoride exposure 2.62 mg m-3),

was evaluated by the National Institute for

Occupational Safety and Health (1977).

Within the group of workers with increased

bone density, 60.9% of the urine samples

contained fluoride at concentrations of

4.0 mg L-1 or greater, compared with 47.5%

of the samples submitted by the group of

workers without increased bone density.

This difference was significant (ranging from

p < 0.02 to p < 0.08). The average fluoride

concentrations in urine for the increased

bone density group and the group without an
Science Assessment Document for HF 70 CEPA/FPAC WGAQOG July 1996

increase were 5.12 and 4.53 mg L-1,

respectively. These results demonstrate an

association between increased fluoride

concentrations in the urine and an increase

in suspected cases of osteosclerosis.

Kaltreider et al. (1972) reported the results of

roentgenographic examinations and urinary

fluoride studies of potroom workers in two

aluminum plants. In one plant, 76 of 79

potroom workers X-rayed revealed increased

bone density. Forty-six (58.2%) were

classified as having slight fluorosis, showing

only accentuation of trabeculation and slight

blurring of the bone structure; four (5.1%)

had moderate diffuse structureless bone

appearance; and 26 (32.9%) were classified

as having marked fluorosis. Limited motion

of the dorsolumbar spine was found in 22

(20.6%) of the entire group of 107 potroom

workers and in none of the control group.

The average fluoride exposure (eight-hour

working day) for the potroom workers ranged

from 2.4 to 6.0 mg m-3. The average urinary

fluoride concentration in spot samples

ranged from 8.7 to 9.6 mg L-1. The average

urinary fluoride excretion for the controls was

0.7 mg L-1. The investigation in the second

potroom plant revealed no useful information

on possible toxic effects caused by exposure

to airborne fluorides.

Massmann (1981) reviewed occupational

epidemiological studies on fluorine and its

inorganic fluorides. In Germany, the

threshold limit values were reported to be

0.1 ppm for fluorine, 3 ppm for hydrogen

fluoride (2.5 mg m-3) and 2.5 mg m-3 for

fluoride. Exceedances of these threshold

limit values may lead to toxic effects and

disease, such as fluorosis. Fluorosis is

characterized by stiffness and immobility of

the spine and "rheumatic" pains in the back

and extremities. The most sensitive effect of

long-term exposure to fluoride at levels

above the threshold limit value is skeletal

alterations, or osteosclerosis. Following this

effect, exostosis and calcinoses of the

ligaments occur.

In Germany, fluorosis with skeletal

alterations rarely occurs. In a study in which

urine samples of individuals exposed to 2.4

ppm airborne fluoride for eight hours were

measured, it was concluded that the fluoride

concentration in urine increased in the first

two hours from 0.5 to 4 mg L-1 and in the

next 10 hours to 8 mg L-1; it then decreased

in the next 12 hours to the initial

concentration (Rye, 1961; Massmann 1981).

Based on these observations, Massmann

(1981) proposed a limit for fluoride of 7.0 mg

L

-1 in a 24-hour urine sample.

In a study of 1,242 employees in an

aluminum smelter using the Soderburg

process, Carnow and Conibear (1981)

reported that clinical musculoskeletal effects

can occur before skeletal fluorosis becomes

apparent radiologically. Questionnaire

responses suggested an increased incidence

of musculoskeletal diseases with increasing

total fluoride exposure during employment.

On the other hand, X-rays of the chest and

lumbar spine failed to indicate any

differences related to the exposure index.

As recognized by the authors of this paper,

this group of workers was heterogeneous,

chemical exposures were mixed and

ergonomic problems might have occurred.

Unfortunately, the fluoride levels and the

lengths of exposure were not reported, thus

making a dose–response relationship

impossible to determine. The employees of

the same smelter were examined four years

later by Chan-Yeung et al. (1983). The

exposure levels were determined, and two

control groups were examined. The fluoride
Science Assessment Document for HF 71 CEPA/FPAC WGAQOG July 1996

exposure level in the potroom was about

0.5 mg m-3 for the subgroup with the highest

exposure. The authors were not able to

confirm the finding of Carnow and Conibear

(1981) that clinical musculoskeletal effects

could occur before skeletal fluorosis

becomes apparent radiologically.

It has been suggested that no discernible

radiological or clinical signs of osteosclerosis

will appear if the air concentrations of

inorganic fluoride in the workplace remain

below 2.5 mg m-3 and the urinary fluoride

concentration of workers does not exceed

4 mg L-1 pre-shift (collected at least 48 hours

after previous occupational exposure) and

8 mg L-1 post-shift over long periods of time

(Dinman et al., 1976a; Hodge and Smith,

1977). U.S. recommendations for the

threshold limit value for air fluoride have

been established on the basis of these data

(National Institute for Occupational Safety

and Health, 1977). However, some countries

recommend lower values. The former Soviet

Union recommended 1.0 mg m-3 as the

threshold limit value for air fluoride

concentrations expressed as hydrogen

fluoride (Gabovich and Ovrutskiy, 1969;

International Labour Organization, 1980;

U.S. Environmental Protection Agency,

1980). The correlation between fluoride

levels in the ambient air, fluoride levels in the

urine and the development of skeletal

changes needs further documentation

(World Health Organization, 1984).

In a few individual cases of human exposure

to a high concentration of airborne hydrogen

fluoride, mottling of the teeth was described

(Heitman, 1976; World Health Organization,

1984). No other cases of dental fluorosis

after exposure to airborne fluorides have

been reported. The exposure levels at which

these effects occur have not been provided.

7.3.2.3 Effects on Kidneys

There are no clear indications from clinical

case studies or epidemiological studies that

airborne hydrogen fluoride or other fluorides

cause nephrotoxicity. Therefore, a NOAEL

relating to potential nephrotoxicity for

airborne hydrogen fluoride or other fluorides

cannot be established. The information on

potential nephrotoxicity comes from studies

on humans exposed orally or parenterally to

hydrogen fluoride, other fluorides or fluorine

compounds.

In cryolite workers, Roholm (1937) found

only insignificant haematuria and no

albuminuria. A possible relationship between

albuminuria and fluoride exposure was

suggested by Derryberry et al. (1963), but

Kaltreider et al. (1972) were unable to show

any chronic effects on the kidney. No renal

disorder has been related to fluoride in areas

of endemic fluorosis (Jolly et al., 1969) or to

cases of industrial fluoride exposure (Dinman

et al., 1976b; Smith and Hodge, 1979). No

cases of renal signs or symptoms are

mentioned in connection with prolonged

intake of fluoride in the treatment of

osteoporosis and osteospongiosis (Causse

et al., 1980; Schamschula, 1981; Dixon,

1983), although a thorough examination of

kidney function may not have been carried

out. No indications of increased frequency of

kidney diseases or disturbed kidney

functions have been recognized in areas

with fluoride concentrations in water of 8 mg

L

-1 (Leone et al., 1954, 1955), 2.0–5.6 mg L-1

(McClure, 1946; Geever et al., 1958) and 1.0

mg L-1 (Summens and Keitzer, 1975).

Although there are no reports of fluorideinduced chronic renal disorders in healthy

individuals, several studies have dealt with

the possible influence of fluoride on people

with manifest kidney diseases. In patients
Science Assessment Document for HF 72 CEPA/FPAC WGAQOG July 1996

with kidney failure, fluoride excretion is

decreased, and the ionic plasma fluoride

concentration is higher than normal (Juncos

and Donadio, 1972; Berman and Taves,

1973; Hanhijaervi, 1974). The capacity of the

skeleton to store fluoride may provide a

sufficient safety margin (Hodge and Smith,

1954; Hodge and Taves, 1970). On the other

hand, it also seems plausible that an

increased plasma fluoride concentration may

result from fluoride liberation from the bone

resorption process involved in certain kidney

diseases. Patients with diabetes insipidus

may absorb excess amounts of fluoride

because of the large quantities of fluids

ingested (World Health Organization, 1984;

Thiessen, 1988).

In the case of fluoride-containing anaesthetic

agents, nephrotoxic effects were discovered

as a side-effect related to the metabolites of

methoxyflurane or enflurane (Hagood et al.,

1973; World Health Organization, 1984).

Kidney damage is related to the high serum

levels of fluoride and may show up days

after anaesthesia.

Although peak fluoride levels associated with

acute nephrotoxic effects have frequently

been higher than 50 μg L-1, the total dose

may be of more importance (Marier, 1982).

Changes in kidney function have been

reported at lower fluoride levels (Jarnberg et

al., 1979). At serum fluoride levels averaging

about 6 μmol/L after enflurane anaesthesia,

no nephrotoxic effects were seen, but blood

and urine levels of phosphorus changed

considerably (Duchassing et al., 1982). It is

not yet clear whether this circulating fluoride

is directly related to the nephrotoxicity or

whether fluoride is only indicative of

metabolites of enflurane and methoxyflurane

that formed during the biotransformation and

that caused the nephrotoxicity. Therefore,

these data are difficult to apply to the case of

exposure to airborne hydrogen fluoride or

other fluorides and the possibility of induction

of nephrotoxicity.

An important finding of the previous studies

is that people already suffering from

insufficient kidney function might be at risk

from the toxic effects of fluorides owing to a

decreased elimination of fluoride.

7.3.2.4 Carcinogenicity

No specific epidemiological evidence is

available on 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 production,

fluorspar mining and stainless steel pickling

(de Villiers and Windish, 1964; Ahlborg et al.,

1981; World Health Organization, 1984;

Grandjean et al., 1985). 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 (de Villiers and Windish, 1964; Drury

et al., 1980; Ahlborg et al., 1981; World

Health Organization, 1984; Grandjean et al.,

1985). A 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; Thiessen, 1988).

The possible carcinogenic potential of

fluoride in drinking water has been

investigated by comparing rates of cancer in
Science Assessment Document for HF 73 CEPA/FPAC WGAQOG July 1996

areas with artificially and naturally fluoridated

water. 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 U.S.

National Academy of Sciences (1977) and

the U.S. Environmental Protection Agency

(1985) also agreed that the available

information does not suggest that fluoride in

drinking water has increased the rate of

cancer mortality. The U.S. Environmental

Protection Agency (1985) stated that "there

is not enough information to conclude that

fluoride presents a cancer risk to humans,"

but it has not officially classified fluoride or

hydrogen fluoride with respect to

carcinogenicity (Thiessen, 1988).

7.3.2.5 Reproductive Effects and

Teratogenicity

Few reports are available concerning

industrial fluoride exposure of women. The

one available epidemiological study of

female workers in a superphosphate plant

found a higher incidence of gynaecological

problems (e.g., menstrual irregularities,

vaginal and uterine inflammation, toxicosis

during pregnancy, untimely discharge of

amniotic fluid) in production workers than in

the control group of office workers and

housewives (Hodge and Smith, 1977; Smith

and Hodge, 1979). The production workers

were exposed to dust concentrations of 5–57

mg m-3 and fluoride concentrations of 0.8–

2.8 mg m-3 but specific information is not

available on the possible correlation of

gynaecological 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-1 or more in drinking water (Hodge

and Smith, 1977; Smith and Hodge, 1979).

The U.S. Environmental Protection Agency

(1985) concluded that there is inadequate

evidence to support an association between

fluoride in U.S. drinking water and either

reproductive or teratogenic effects

(Thiessen, 1988).

7.3.2.6 Other Health Effects

Other effects of chronic fluoride exposure in

humans have been reported occasionally,

including thyroid injury, anaemia,

hypersensitivity and dermatological reactions
Science Assessment Document for HF 74 CEPA/FPAC WGAQOG July 1996

(Spira, 1944; Hodge, 1960; Waldbott, 1961,

1973, 1980, 1981; McLaren, 1976; Waldbott

and Lee, 1978). None of these effects has

been convincingly established, particularly

for fluoride concentrations likely to be

encountered by the general public (Princi,

1960; Kaltreider et al., 1972; U.S. National

Academy of Sciences, 1977; Smith and

Hodge, 1979; World Health Organization,

1984; U.S. Environmental Protection

Agency, 1985). The U.S. Environmental

Protection Agency (1986) established an oral

Reference Dose for fluoride of 0.06 mg kg-1

body weight per day for children, an intake

that corresponds to a fluoride level of 1 mg L1

 (1 ppm) in water. Neither dental nor skeletal

fluorosis occurs at this level. An inhalation

reference dose is not available (Thiessen,

1988).

7.4 SUMMARY OF HEALTH

EFFECTS OF INORGANIC

FLUORIDES AS REPORTED BY

CEPA

Inorganic fluorides, including gaseous

fluorides, were assessed as part of the

requirements of the Canadian Environmental

Protection Act (CEPA) (Government of

Canada, 1993). Carcinogenic effects of

inorganic fluorides were reviewed in a large

number of ecological studies, in studies with

laboratory animals and in epidemiological

studies. The CEPA report concluded that the

available data are inadequate to assess

carcinogenicity in humans. This conclusion

supports earlier conclusions by the

International Agency for Research on Cancer

(1982), the World Health Organization

(1984) and the U.S. Environmental

Protection Agency (Thiessen, 1988).

There is evidence that fluoride is genotoxic,

based on the outcome of in vitro and in vivo

studies. Sodium fluoride induced recessive

lethal mutations in Drosophila melanogaster

and cytogenetic damage after intraperitoneal

injections in rodents. Generally, however, in

studies in which fluoride was administered to

laboratory animals by routes of exposure

similar to those by which humans are

normally exposed (i.e., orally), fluoride had

no effect upon the frequency of

chromosomal aberrations, micronuclei, sister

chromatid exchange, DNA strand breaks or

sperm morphology. The mechanism by

which sodium fluoride induces genetic

alterations is not known; however, it is not

likely due to an interaction between the

fluoride ion and DNA. Rather, it may be a

secondary effect of the actions of fluoride

that results from its inhibition of enzymes

involved in DNA synthesis and/or repair.

(Government of Canada, 1993)

Because there are inconclusive data on the

carcinogenic effects of inorganic fluoride and

because inorganic fluoride is not directly

genotoxic to DNA, the CEPA assessment

(Government of Canada, 1993) based its

toxicological evaluation on the NOAEL for

the most sensitive phenomenon in long-term

studies in both laboratory animals and

humans. Based on the available data, it is

evident that, following long-term exposure,

skeletal effects in humans occur at dose

levels of exposure lower than those

associated with other adverse health effects,

which is likely a consequence of the

accumulation of inorganic fluoride almost

exclusively in bone. Therefore, effects on the

skeleton are considered to be the most

relevant in assessing the toxicological effects

of long-term exposure to inorganic fluorides.

The lowest reported NOAEL for effects of

fluoride on the skeleton in Sprague-Dawley
Science Assessment Document for HF 75 CEPA/FPAC WGAQOG July 1996

rats was 1.8 mg kg-1 body weight per day

(and for Fischer-344 rats, 2.7 mg kg-1 body

weight per day). However, rats are generally

considered to be less sensitive than humans

or larger animals to the toxicological effects

of fluorides, owing to differences in

toxicokinetics and skeletal development.

Dogs and pigs are considered more

appropriate models for the examination of

the potential effects of various agents on the

skeleton in humans. However, only shortterm experiments with fluorides in dogs and

pigs have been performed. Administration of

fluoride at 0.32 and 2 mg kg-1 body weight

per day to dogs and pigs, respectively, did

not cause overtly pathological effects on the

bone or on the general health of the animals.

Owing to the availability of data, although

limited, on exposure–response relationships

in humans and the interspecies variations in

response to fluoride, the results of

epidemiological studies on the effects of

fluoride in humans were taken into account

in the derivation of an effect level for

inorganic fluoride. Case reports or

descriptive ecological studies of skeletal

fluorosis or osteosclerosis were not

adequately documented. There is also

limited quantitative information on exposure

to inorganic fluoride and the development of

skeletal effects in occupationally exposed

workers (Government of Canada, 1993).

Inconsistent results of inherently limited

cross-sectional studies of small populations

exposed to often unspecified concentrations

of fluoride in the vicinity of industrial sources

contribute little to an assessment of an

exposure–response relationship for skeletal

effects associated with exposure to fluoride.

Information obtained from clinical studies, in

which sodium fluoride was administered to

patients for the treatment of osteoporosis,

was considered to be inadequate, owing to

the limitations of the protocol and

characteristics of the patients in these

studies. Moreover, these clinical studies

were undertaken to assess the considered

beneficial effects. There are also limitations

in the experimental design of epidemiological

investigations. In addition, owing to the lack

of data on individual exposures in

epidemiological studies, it is difficult to derive

meaningful conclusions concerning the

exposure–response relationship for possible

skeletal effects associated with exposure to

fluoride.

Estimating an effects threshold for the

development of skeletal fluorosis (or related

changes) in humans exposed to inorganic

fluoride is further complicated by differences

in the radiological diagnosis of early-stage

skeletal fluorosis among health care

professionals, as well as by the multiplicity of

factors that may influence the amount of

fluoride deposited in bones. (Government of

Canada, 1994)

Nevertheless, considering the limitations of

human studies and complicating factors

involved, when the results are evaluated

collectively, the available data indicate that

potentially adverse effects associated with

skeletal fluorosis are likely to be observed at

fluoride intakes greater than approximately

200 μg kg-1 body weight per day. Although

the relative risk of hip, wrist or spinal fracture

was increased in some groups of women

residing in an elevated fluoride community

(72 μg kg-1 body weight per day) compared

with control communities, the estimated

intake of fluoride by these women was likely

underestimated, and the calcium intake was

only 25% from normal. It is concluded,

therefore, on the basis of available data, that

skeletal fluorosis is likely to be observed at

intakes greater than approximately
Science Assessment Document for HF 76 CEPA/FPAC WGAQOG July 1996

200 μg kg-1 body weight per day. Moreover,

predicted concentrations of fluoride in bone

resulting from a daily fluoride intake of

200 μg kg-1 body weight per day or higher

are within the range of those reported to be

associated with effects on the skeleton

(Government of Canada, 1993).

Based on the limited available data, adverse

effects upon haematopoietic, hepatic or renal

function are not expected to occur at this

fluoride intake level of 200 μg kg-1 body

weight per day, but at fluoride levels of about

387 μg kg-1 body weight per day or higher.

There are insufficient quantitative data

available from studies in humans from which

to conclude unequivocally that exposure to

this level of inorganic fluoride would have

adverse effects upon human reproduction

and development or on the central nervous

and immune systems (Government of

Canada, 1993).

The CEPA report concluded that, based

on available information, the estimated

average daily intakes of inorganic fluoride,

which range from approximately 0.5 to

160 μg fluoride by various age groups

in the general population (or up to

167 μg fluoride/kg bw/day by those in

the vicinity of point sources of inorganic

fluorides) are less than the level

(200 μg fluoride/kg bw/day) at which

adverse effects upon the skeleton (most

sensitive end-point on the basis of available

data in humans) are

anticipated.(Government of Canada, 1993)

7.5 HUMAN EXPOSURE

ASSESSMENT

Fluorides exist in both gaseous and

particulate forms. In Canada, ambient

concentrations of gaseous fluorides are

relatively low and are not expected to pose

a significant problem with respect to human

exposure in the general population.
Science Assessment Document for HF 77 CEPA/FPAC WGAQOG July 1996

The levels of fluoride in ambient air in most

parts of Canada are generally low or

undetectable (i.e., <0.05 μg m-3), although

available data are limited. the average

(monthly) mean concentration of fluoride in

an unspecified number of samples of

ambient air collected from as residential area

in Toronto, Ontario (January 1981 – July

1981), was 0.03 μg m-3 (detection limit not

specified) (McGrath, 1983). This is similar to

the mean fluoride concentration of <0.05 μg

m

-3 (detection limit 0.05 μg m-3) reported for

4,411 samples of ambient air collected in

1968 from 29 rural and 147 non-industrial

urban locations throughout the United

States; fluoride was not detected in any of

the rural samples (n=724), whereas the

concentration of fluoride in urban air

(n=3687) ranged from <0.05 to 1.65 μg m-3,

(Government of Canada, 1993).

For additional information on environmental

levels of hydrogen fluoride in Canada, refer

to section 3.4.

Higher ambient concentrations of gaseous

fluorides may be observed in the immediate

vicinity of industrial sources. Monitoring data

indicate that ambient air concentrations

measured in the vicinity of fluoride-emitting

industries can be up to an order of

magnitude greater than concentrations in

ambient air sampled at other locations.

Industrial sources found to release gaseous

fluorides include aluminum smelters, steel

plants and phosphorus plants. These

sources have been monitored in 11 locations

across Canada and are listed in table 5.

Monitoring data for gaseous fluorides in air

surrounding industries clearly show

concentrations much higher than in rural and

urban areas. Mean concentrations are

approximately 1.0 μg m-3. Concentrations as

high as 23.08 μg m-3 have also been

recorded (Environment Canada, 1988,

1989).

No information on the concentration of

fluoride in the indoor air of homes within

Canada has been identified (Government of

Canada, 1993). It may be assumed that

some gaseous fluorides enter the indoor air

environment in conjunction with the

infiltration of outdoor air.
Science Assessment Document for HF 78 CEPA/FPAC WGAQOG July 1996

The estimated upper bound of daily intake of

gaseous fluorides from ambient air by five

age groups of Canadians in several locations

across the country are shown in table 9

(McGrath, 1983; Health and Welfare

Canada, 1992; Government of Canada,

1993; Government of Canada, Supporting

Documentation, 1993; Environment Canada,

1994).

Table 9 Estimated upper bound of daily intake of gaseous fluorides

Age and daily intake (μg/kg body weight per day)

Location

Mean

conc. in air

(μg m-3)

0–6

monthsa

7 months

– 4 yearsb

5–11

yearsc

12–19

yearsd

20+ yearse

Ambient airf0.03g0.01 0.01 0.01 0.01 0.01

Cornwall, Ont. 0.79 0.23 0.30 0.35 0.29 0.26

Cornwall, Ont. 0.85 0.24 0.33 0.38 0.31 0.28

Cornwall, Ont. 0.43 0.12 0.17 0.19 0.16 0.14

Toronto, Ont. 0.07 0.02 0.03 0.03 0.03 0.02

Brampton, Ont. 0.73 0.20 0.28 0.32 0.27 0.24

Long Harbour, Nfld. 0.15 0.04 0.06 0.07 0.06 0.05

Long Harbour, Nfld. 0.14 0.04 0.05 0.06 0.05 0.05

Trail, B.C. 0.59 0.17 0.23 0.26 0.22 0.19

Arvida, Que. 0.67 0.19 0.26 0.30 0.25 0.22

Grande Baie, Que. 0.10 0.03 0.04 0.04 0.04 0.03

Laterrière, Que. 0.14 0.04 0.05 0.06 0.05 0.05

Beauharnois, Que. 0.10 0.03 0.04 0.04 0.04 0.03

a

 Assumed to weigh 7 kg and breathe 2 m3 air per day (Health and Welfare Canada, 1992).

b

 Assumed to weigh 13 kg and breathe 5 m3 air per day (Health and Welfare Canada, 1992).

c

 Assumed to weigh 27 kg and breathe 12 m3 air per day (Health and Welfare Canada, 1992).

d

 Assumed to weigh 57 kg and breathe 21 m3 air per day (Health and Welfare Canada, 1992).

e

 Assumed to weigh 70 kg and breathe 23 m3 air per day (Health and Welfare Canada, 1992).

f

 See table 3, "Ambient Air," in Government of Canada (1993).

g

 Based on a mean concentration of inorganic (gaseous and particulate) fluoride in ambient air of 0.03 μg m-3, reported for

 Toronto, Ontario (McGrath, 1983), and assuming the concentration in indoor air is identical to that in outdoor (ambient) air.

7.6 SUMMARY AND CONCLUSION

Inhaled fluorides are rapidly absorbed in the

upper respiratory tract; close to 100% of

inhaled hydrogen fluoride is absorbed. The

fate and effects of absorbed fluorides are

essentially independent of the fluoride

source or the route of exposure. About 50%

of absorbed fluoride is retained in the body.

Approximately 99% of the fluoride in the

body is found in the skeleton; the remainder

is distributed in soft tissues. The half-life for
Science Assessment Document for HF 79 CEPA/FPAC WGAQOG July 1996

uptake by bone tissue is very short (about

13 minutes). A portion of circulating fluoride

(50%) is inorganic fluoride, and the

remainder consists of organic fluorides. The

inorganic fluoride content increases with the

fluoride exposure level. The other half of

absorbed fluoride is rapidly eliminated from

the body. The majority is excreted by urine,

and only a few percent is excreted in faeces

and sweat. Urinary excretion of fluoride is

decreased in cases of renal dysfunction. In

pregnant women, fluoride crosses the

placenta. Measurement of fluoride in serum,

urine or bone can under certain conditions

serve to monitor exposure to gaseous

fluorides.

The pharmacodynamics of fluoride are

characterized by fluoride's effects on many

enzyme systems and their complexing effect

on metal ions. At high exposure levels, these

properties result in several effects such as

cardiovascular collapse, hypocalcaemia,

hyperkalaemia and skeletal alterations.

Concentrations of gaseous fluorides in air

that may pose a concern to human health

have been reviewed in the CEPA

Assessment Report for Inorganic Fluorides

(Government of Canada, 1993), as well as a

contract report on the health effects of

gaseous fluorides prepared for Health

Canada (Speijers, 1995). Health effects in

experimental studies are generally observed

at dose concentrations more than 100 times

mean concentrations found in ambient air.

Studies in humans have revealed a NOAEL

of 0.9 mg m-3 of airborne hydrogen fluoride

for skin and eye irritation and a NOAEL of

2.1 mg m-3 as fluoride for irritation of the

respiratory tract. The odour threshold for

hydrogen fluoride ranges from 0.02 to

0.22 mg m-3.

Clinical studies and most epidemiological

studies on the inhalation of fluorides are not

adequately designed to allow a NOAEL for

systemic effects to be derived or a clear

effect level to be identified. In many cases,

individual exposures to fluorides in ambient

air were not monitored. In workplace studies,

people are exposed to many other potentially

toxic compounds in addition to gaseous and

particulate fluorides in the ambient air,

making it impossible to establish an

indicative NOAEL for gaseous fluorides. Only

a few chronic epidemiological studies

provide some quantitative information on

exposure levels indicative of toxic effects on

the skeleton (fluorosis and osteosclerosis)

and the respiratory tract. In humans, no

effects of chronic exposure to airborne

hydrogen fluoride on kidneys, brain, thyroid

or the haematopoietic system have been

convincingly established at exposure levels

considered to be representative of those

normally encountered in ambient air or

causing skeletal alterations or effects on the

respiratory tract. No specific epidemiological

data on the carcinogenic effects of airborne

fluoride are available. A definitive NOAEL for

airborne fluoride, including hydrogen

fluoride, cannot be established from the

available studies.

For intake of fluorides by other exposure

routes, it has been concluded by several

review bodies that there is insufficient

evidence concerning any carcinogenic

properties of inorganic fluorides. In addition,

there is inadequate evidence to support an

association between exposure to fluorides by

different exposure routes and reproductive or

teratogenic effects. As it is known from oral

studies that, at least for skeletal alterations,

rats are less sensitive than humans, it is

prudent to rely mainly on the toxicological

data in humans for a toxicological evaluation.
Science Assessment Document for HF 80 CEPA/FPAC WGAQOG July 1996

Both for laboratory animals and for humans,

it can be concluded that adequate

toxicological studies with gaseous fluorides

(including hydrogen fluoride) are very limited.

From studies in occupationally exposed

adults, it can be concluded that, in general,

exposure to airborne hydrogen fluoride levels

below 1.78–2.5 mg m-3 for an eight-hour

work day will not cause skeletal alterations.

The occupational exposure limit for fluoride

of 2.0 mg m-3 per eight-hour shift

corresponds to a fluoride intake of 286 μg

kg-1 body weight per day for a 70-kg adult

exposed to an equivalent concentration in

ambient air for 24 hours. This, then, is a

NOAEL for skeletal effects. This can be

compared with the CEPA report's conclusion

(Government of Canada, 1993) that

potentially adverse effects associated with

skeletal fluorosis are likely to be observed at

fluoride intakes above about 200 μg kg-1

body weight per day. Pulmonary effects, the

most sensitive effect, are reported to appear

in children, the most sensitive receptor, at

gaseous fluoride concentrations above 200

μg m-3 (and 300 μg m-3 for particulate

fluoride). This concentration can be

considered a LOAEL for children (Turner et

al., 1993).

The ambient air concentration of gaseous

fluoride ranges from <0.05 to 1.65 μg m-3 in

Canada and the United States. In most parts

of Canada, the exposure levels are below

0.05 μm m-3. Ambient exposures range from

100 to 10,000 times less than the estimated

effect level derived from human studies.

Children, people with impaired kidney

function, industrially exposed workers and

persons living in the vicinity of a point source

of fluoride emissions may be at somewhat

greater risk than the general population,

although all such groups are expected to be

exposed to concentrations well below the

effect level.
Science Assessment Document for HF 7-81 CEPA/FPAC WGAQOG July 1996
Science Assessment Document for HF 82 CEPA/FPAC WGAQOG July 1996

8 REFERENCES

8.1 COMPREHENSIVE SURVEYS

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American Society for Testing and Materials

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Science Assessment Document for HF 84 CEPA/FPAC WGAQOG July 1996

Boink, A.B.T.J. (1993) Pathophysiological

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IV. Response of livestock and poultry to

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Charkes, N.D., P.T. Marler Jr., and C. Phillips

(1978) Studies of skeletal tracer kinetics. 1.

Digital computer solution of a five

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Science Assessment Document for HF 85 CEPA/FPAC WGAQOG July 1996

Cole, J., W.J. Muriel, and B.A. Bridges

(1986) The mutagenecity of sodium fluoride

to L5178Y [wild type and TK +/- (3.7.2)]

mouse lymphoma cells. Mutagenesis

1:157-167.

Collings, G.H. Jr., R.B.L. Fleming, R. May,

and W.O. Bianconi (1952) Absorption and

excretion of inhaled fluorides–further

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Science Assessment Document for HF 104 CEPA/FPAC WGAQOG July 1996

APPENDIX HF REFERENCE DOSE DATABASE
Appendix HF Reference Dose Database

Study 

No. Author(s) Year Journal Vol. pg Species Cultivar Life Stage Age

Conc. 

(μg m-3)

1 Adams, D.F., C.G. Shaw, and W.D. 

Yerkes Jr.

1956 Phytopathology 46 587-591 Gladiolus Ethyl Cave Cole 4th true leaf 0.85

1 Adams, D.F., C.G. Shaw, and W.D. 

Yerkes Jr.

1956 Phytopathology 46 587-591 Gladiolus Ethyl Cave Cole 4th true leaf 1.46

1 Adams, D.F., C.G. Shaw, and W.D. 

Yerkes Jr.

1956 Phytopathology 46 587-591 Ponderosa Pine 

(Pinus ponderosa )

needles 50% 

exposed

5 yr 1.46

2 Solberg, R.A., D.F. Adams, and H.A. 

Ferchau

1955 Proceedings of the Third National 

Air Pollution Symposium

164-176 Ponderosa Pine 

(Pinus ponderosa )

4ft tall 0.61

2 Solberg, R.A., D.F. Adams, and H.A. 

Ferchau

1955 Proceedings of the Third National 

Air Pollution Symposium

164-175 Ponderosa Pine 

(Pinus ponderosa )

4ft tall 0.20

3 MacLean, D.C., R.E. Schneider, 

and D.C. McCune

1977 J. Amer. Soc. Hort. Sci. 102(3) 297-299 Green bean 

(Phaseolus vulgaris 

L.)

Tendergreen life span 0.60

3 MacLean, D.C., R.E. Schneider, and 

D.C. McCune

1977 J. Amer. Soc. Hort. Sci. 102(3) 297-299 Tomato 

(Lycopersicon 

esculentum )

Fireball life span 0.60

4 Zwiazek, J.J. 1994 Ontario Ministry of Environment 

and Energy, Research Technology 

Branch, PIBS 2807, ISBN 0-7778-

0383-6

White pine (Pinus 

strobus L.)

seedlings 9 wks 0.61

4 Zwiazek, J.J. 1994 Ontario Ministry of Environment 

and Energy, Research Technology 

Branch, PIBS 2807, ISBN 0-7778-

0383-6

White pine (Pinus 

strobus L.)

seedlings 9 wks 2.44

4 Zwiazek, J.J. 1994 Ontario Ministry of Environment 

and Energy, Research Technology 

Branch, PIBS 2807, ISBN 0-7778-

0383-6

White pine (Pinus 

strobus L.)

seedlings 9 wks 0.61

5 MacLean, D.C., and R.E. Schneider 1981 Environmental Pollution (Series A) 24 39-44 Wheat (Triticum 

aestivum L.)

Olaf anthesis 0.90

5 MacLean, D.C., and R.E. Schneider 1981 Environmental Pollution (Series A) 24 39-44 Wheat (Triticum 

aestivum L.)

Olaf boot stage 0.90

6 MacLean, D.C., R.E. Schneider, 

and L.H. Weinstein

1982 Environmental Pollution (Series A) 29 27-34 Jerusalem cherry 

(Solanum pseudocapsicum L.)

3 months 0.90

7 Madkour, D., and L.H. Weinstein 1987 Environmental Toxicology and 

Chemistry

6 627-634 Soybean (Glycine 

max L.)

Hodgson veg. growth 0.70

7 Madkour, D., and L.H. Weinstein 1987 Environmental Toxicology and 

Chemistry

6 627-633 Soybean (Glycine 

max L.)

Hodgson veg. growth 3.50

8 Coulter, C.T., M.R. Pack, and C.W. 

Sulzbach

1985 Atmospheric Environment 19 (6) 1001-

1007

Gladiolus Snow Velvet 2 to 3 leaf stage 31 days old 2.90

8 Coulter, C.T., M.R. Pack, and C.W. 

Sulzbach

1985 Atmospheric Environment 19 (6) 1001-

1007

Gladiolus T210 2 to 3 leaf stage 31 days old 2.90

8 Coulter, C.T., M.R. Pack, and C.W. 

Sulzbach

1985 Atmospheric Environment 19 (6) 1001-

1007

Gladiolus T210 2 to 3 leaf stage 31 days old 2.90

8 Coulter, C.T., M.R. Pack, and C.W. 

Sulzbach

1985 Atmospheric Environment 19 (6) 1001-

1007

Gladiolus T210 2 to 3 leaf stage 31 days 

old

2.90

8 Coulter, C.T., M.R. Pack, and C.W. 

Sulzbach

1985 Atmospheric Environment 19 (6) 1001-

1007

Gladiolus T210 2 to 3 leaf stage 31 days 

old

2.90

Note: Scientific Data Used to Derive the Reference Levels is Indicated in Bold Face Type

Science Assessment Document for HF 98 CEPA/FPAC WGAQOG July 1996
Appendix HF Reference Dose Database

Study 

No.

1

1

1

2

2

3

3

4

4

4

5

5

6

7

7

8

8

8

8

8

Duration 

(days) Dose Dose Period Protocol Endpoint Measured Effect Significant (p<=.05) Variability Comments

1.00 0.85 1 standard 

chamber

leaf necrosis, inj. 

index=0.7

Yes - - Conc. in paper expressed as ppb (v/v?). Converted to μg m-3 

by x 1.22. Leaf injury index = % of leaf length injured.

1.00 1.46 1 standard 

chamber

leaf necrosis, inj. 

index=1.9

Yes - - Conc. in paper expressed as ppb (v/v?). Converted to μg m-3 

by x 1.22. Leaf injury index = % of leaf length injured.

1.00 1.46 1 standard 

chamber

leaf necrosis, inj. 

index=0.5

Yes - - Conc. in paper expressed as ppb (v/v?). Converted to μg m-3 

by x 1.22. Leaf injury index = % of leaf length injured.

6.60 4.03 7 standard 

chamber

time to first injury Yes - 20% Conc. in paper expressed as ppb (v/v?). Converted to μg m-3 by 

x 1.22. Duration is average time to first injury on 5 plants. 

Treatment concentrations not measured. Dose includes periods 

between exposures.

19.80 4.03 30 standard 

chamber

time to first injury Yes - 56% Conc. in paper expressed as ppb (v/v?). Converted to μg m-3 by 

x 1.22. Duration is average time to first injury on 5 plants. 

Treatment concentrations not measured. Dose includes periods 

between exposures.

43.00 25.80 30 standard 

open-top

25% (F.W.) 

marketable yield loss

Yes 0.01 -

93.00 55.80 90 standard 

open-top

growth, fruiting, fruit 

production

No - -

2.00 1.22 1 standard 

chamber

increased plasma 

membrane leakage

Yes - - Conc. in paper expressed as ppb (v/v?). Converted to μg m-3 

by x 1.22.

5.00 12.20 7 standard 

chamber

first injury Yes - - Conc. in paper expressed as ppb (v/v?). Converted to μg m-3 

by x 1.22.

20.00 12.20 30 standard 

chamber

first injury Yes - - Conc. in paper expressed as ppb (v/v?). Converted to μg m-3 

by x 1.22.

4.00 3.60 7 standard 

open-top

yield loss Yes 0.05 -

4.00 3.60 7 standard 

open-top

yield loss Yes 0.05 -

1.00 0.90 1 standard 

chamber

leaf necrosis Yes - - Injury occured when exposed in the dark and then brought 

into light. Lowest dose presented which caused an effect.

9.00 6.30 7 standard 

open-top

reduced C 

translocation

No 0.05 - Non-sensitive endpoint.

9.00 31.50 7 standard 

open-top

reduced C 

translocation

Yes 0.05 - Non-sensitive endpoint.

16 of 32 days 31.67 30 standard 

chamber

Overall average of 

5.6% leaf area necrosis

- - Approx. 2 μg m-3/48hr with 48hr no exposure for 32 days. No 

control (non-fumigated) for comparison and detection of a 

significant effect.

16 of 32 days 45.83 

(average)

30 standard 

chamber

Overall average of 

11.1% leaf area 

necrosis.

- - Approx. 2 μg m-3/48hr with 48hr no exposure for 32 days. No 

control (non-fumigated) for comparison and detection of a 

significant effect.

16 of 32 days 45.63 

(average)

30 standard 

chamber

Average of 10.8% leaf 

area necrosis.

- - Alternating 48 hr fumig. w/ 48 hr. non-fumig., total of 8 

fumigations during the 32 day period. No control (non-fumig.), 

therefore, there's no way of knowing if the effect observed is 

statistically significant.

16 of 32 days 45.63 

(average)

30 standard 

chamber

16.7% leaf area 

necrosis.

Yes 0.05 - Alternating 96 hr fumig. w/ 96 hr non-fumig., total of 5 

fumig. in 32 days. Sign. greater effect than in 24 and 48 hr 

fumigations in preceeding 2 lines. Therefore, this effect 

would be significantly greater than a control, even though a 

control is absent.

16 of 32 days 45.83 

(average)

30 standard 

chamber

15.4% leaf area 

necrosis.

Yes 0.05 - 96 hr fumig., 192 hr non-fumig., 192 hr fumig., 192 hr nonfumig., 96 hr fumig., Sign. greater effect than in intermittent 

24 and 48 hr fumig. above. Therefore, this effect would be 

significantly greater than a control, even though a control is 

absent.

Note: Scientific Data Used to Derive the Reference Levels is Indicated in Bold Face Type

Science Assessment Document for HF 99 CEPA/FPAC WGAQOG July 1996
Appendix HF Reference Dose Database

Study 

No. Author(s) Year Journal Vol. pg Species Cultivar Life Stage Age

Conc. 

(μg m-3)

8 Coulter, C.T., M.R. Pack, and C.W. 

Sulzbach

1985 Atmospheric Environment 19 (6) 1001-

1007

Gladiolus T210 2 to 3 leaf stage 31 days 

old

2.90

9 McCune, D.C., T.L. Lauver, and K.S. 

Hansen

1991 Canadian Journal Forest Research 21 756-761 White spruce (Picea 

glauca Moench.)

early summer 2 yr 2.63

9 McCune, D.C., T.L. Lauver, K.S. 

Hansen

1991 Canadian Journal Forest Research 21 756-761 White spruce (Picea 

glauca Moench.)

early summer 2 yr 5.14

9 McCune, D.C., T.L. Lauver, and K.S. 

Hansen

1991 Canadian Journal Forest Research 21 756-761 Black spruce (Picea 

mariana Mill.)

early summer 2 yr 2.29

10 Murray, F. 1983 J. Amer. Soc. Hort. Sci. 108(4) 526-529 Grapevine (Vitis 

sinifer L.)

Shiraz early fruit to 

harvest

mature 0.17

10 Murray, F. 1983 J. Amer. Soc. Hort. Sci. 108(4) 526-529 Grapevine (Vitis 

sinifer L.)

Shiraz early fruit to 

harvest

mature 0.28

10 Murray, F. 1983 J. Amer. Soc. Hort. Sci. 108(4) 526-529 Grapevine (Vitis 

sinifer L.)

Shiraz early fruit to 

harvest

mature 0.28

11 Murray, F. 1984 Environmental Pollution (Series A) 36 337-349 Grapevine (Vitis 

sinifer L.)

Shiraz growing season mature 0.27

11 Murray, F. 1984 Environmental Pollution (Series A) 36 337-349 Grapevine (Vitis 

sinifer L.)

Shiraz growing season mature 0.27

11 Murray, F. 1984 Environmental Pollution (Series A) 36 337-349 Grapevine (Vitis 

sinifer L.)

Shiraz growing season mature 0.17

11 Murray, F. 1984 Environmental Pollution (Series A) 36 337-349 Grapevine (Vitis 

sinifer L.)

Shiraz growing season mature 0.27

12 Hitchcock, A.E., P.W Zimmerman, 

and R.R. Coe

1962 Contributions from Boyce 

Thompson Institute

21 303-344 Gladious numerous varieties - - 0.16

13 Pack, M.R. 1972 Journal of the Air Pollution Control 

Association

22(9) 714-717 Strawberry Marshall growing season 0.55

13 Pack, M.R. 1972 Journal of the Air Pollution Control 

Association

22(9) 714-717 Strawberry Marshall growing season 0.55

13 Pack, M.R. 1972 Journal of the Air Pollution Control 

Association

22(9) 714-717 Strawberry Marshall growing season 2.00

14 Mandl, R.H., L.H. Weinstein, and 

M. Keveny

1975 Environmental Pollution 9 133-143 Barley (Hordeum 

vulgare L.)

Dickinson seedling 10 days 0.72

14 Mandl, R.H., L.H. Weinstein, and 

M. Keveny

1975 Environmental Pollution 9 133-143 Corn (Zea mays L.) Marcross seedling 10 days 0.63

15 Murray, F., and S. Wilson 1988c Environmental Pollution 55 239-249 Barley (Hordeum 

vulgare L.)

Clipper life span 0.38

15 Murray, F., and S. Wilson 1988c Environmental Pollution 55 239-249 Wheat (Triticum 

aestivum L.)

Halberd life span 0.38

16 Pack, M.R. 1971 Journal of the Air Pollution Controll 

Assoc.

21(3) 133-137 Green bean 

(Phaseolus vulgaris 

L.)

Tendergreen life span 2.10

17 McCune, D.C., A.E. Hitchcock, and 

L.H. Weinstein

1966 Contrib. Boyce Thompson Inst. 23(8) 295-299 Gladiolus Snow Princess 3 leaf stage 4 - 8 wks 2.10

18 Mohamed, A.H., J.D. Smith, and 

H.G. Applegate

1966 Can. J. Genet. Cytol. 8 575-583 Tomato 

(Lycopersicon 

esculentum Mill.)

309-7-1-2 pre-flowering 3.00

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Alfalfa (Medicago 

sativa L.)

Ranger 2.50

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Barley (Hordeum 

vulgare L.)

Bonneville 0.34

Note: Scientific Data Used to Derive the Reference Levels is Indicated in Bold Face Type

Science Assessment Document for HF 100 CEPA/FPAC WGAQOG July 1996
Appendix HF Reference Dose Database

Study 

No.

8

9

9

9

10

10

10

11

11

11

11

12

13

13

13

14

14

15

15

16

17

18

19

19

Duration 

(days) Dose Dose Period Protocol Endpoint Measured Effect Significant (p<=.05) Variability Comments

16 of 32 days 45.83 

(average)

30 standard 

chamber

17.5% leaf area 

necrosis.

Yes 0.05 - 192 hr fumigation, 384 hr non-fumig., 192 hr fumig. Sign. 

greater effect than in intermittent 24 and 48 hr fumig. above. 

Therefore, this effect would be significantly greater than a 

control event though a control is absent.

2.08 5.48 7 standard 

open-top

apical necrosis - - No control for comparison.

2.08 10.71 7 standard 

open-top

16% of trees with 

apical necrosis

- - No control for comparison.

3.25 7.44 7 standard 

open-top

30% of trees with 

apical necrosis

- - No control for comparison.

64.00 10.88 90 standard 

open-top

no necrosis No - -

64.00 17.92 90 standard 

open-top

no yield effect No - -

64.00 17.92 90 standard 

open-top

foliar necrosis on 5% 

of the leaves

- - Marginal response (5% necrosis). No statistical comparison to 

control. No effect on fruit yield or quality.

189.00 51.03 90 standard 

open-top

no yield effect No - -

189.00 51.03 90 standard 

open-top

no yield effect No - -

99.00 16.83 90 standard 

open-top

days to first injury Yes - - Well controlled experiment.

83.00 22.41 90 standard 

open-top

days to first injury Yes - - Well controlled experiment.

9.00 1.44 7 early 

chamber

2.5-6.0 cm tip burn - - Poor statistical treatment of the data. Experiments inadequately 

controlled.

112.00 61.60 90 standard 

chamber

fruit wt. No 0.05 - No significant effect at this dose.

112.00 61.60 90 standard 

chamber

fruit development Yes 0.05 - Difficult to accurately calculate dose from the information 

given.

112.00 224.00 90 standard 

chamber

fruit wt. Yes 0.05 - Difficult to accurately calculate dose from the information 

given.

27.00 19.44 30 standard 

chamber

6.7% leaf necrosis Yes - SD = 5.3%

27.00 17.01 30 standard 

chamber

necrotic lesions on 

leaves increased

Yes 0.001 -

90.00 34.20 90 standard 

open-top

no. of grains/ear 

decreased by 6.25%

Yes 0.05 - Reduced no. of grains/ear offset by increased grain wt. and 

number of tillers.

90.00 34.20 90 standard 

open-top

yield components No - - Wheat is not a sensitive species.

90.00 189.00 90 standard 

chamber

less vigorous F1 

progeny

Yes - - This is not a sensitive endpoint. Statistical treatment of the data 

is weak.

7 of 49 days 14.70 90 standard 

chamber

40 mm leaf tip burn Yes - -

4.00 12.00 7 standard 

chamber

chromosomal 

abnormalities (mitosis 

and meiosis)

Yes - - Treatments >4 days had effects as well. No leaf damage 

observed.

26.00 65.00 30 greenhouse 

fumigation

chlorosis, growth No - -

107.00 36.38 90 greenhouse 

fumigation

chlorosis, growth, 

yield

No - -

Note: Scientific Data Used to Derive the Reference Levels is Indicated in Bold Face Type

Science Assessment Document for HF 101 CEPA/FPAC WGAQOG July 1996
Appendix HF Reference Dose Database

Study 

No. Author(s) Year Journal Vol. pg Species Cultivar Life Stage Age

Conc. 

(μg m-3)

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Sugar beets 0.43

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Bean (Phaseolus 

sp.)

Lima 0.64

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Bean (Phaseolus 

sp.)

Lima 0.40

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Celery 0.89

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Celery 0.66

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Schupe, H.B Peterson, N.C. 

Leone

105-115 Corn (Zea mays L.) 0.41

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Schupe, H.B Peterson, N.C. 

Leone

105-115 Corn (Zea mays L.) 0.47

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Schupe, H.B Peterson, N.C. 

Leone

105-115 Gladiolus 0.66

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Gladiolus 1.38

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Schupe, H.B Peterson, N.C. 

Leone

105-115 Gladiolus 0.36

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Schupe, H.B Peterson, N.C. 

Leone

105-115 Gladiolus 0.48

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Schupe, H.B Peterson, N.C. 

Leone

105-115 Gladiolus 0.44

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Schupe, H.B Peterson, N.C. 

Leone

105-115 Gladiolus 0.70

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Shupe, H.B Peterson, N.C. 

Leone

105-115 Gladiolus 0.50

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Schupe, H.B Peterson, N.C. 

Leone

105-115 Gladiolus 0.41

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Onion (Alium ) growing season 1.12

Note: Scientific Data Used to Derive the Reference Levels is Indicated in Bold Face Type

Science Assessment Document for HF 102 CEPA/FPAC WGAQOG July 1996
Appendix HF Reference Dose Database

Study 

No.

19

19

19

19

19

19

19

19

19

19

19

19

19

19

19

19

Duration 

(days) Dose Dose Period Protocol Endpoint Measured Effect Significant (p<=.05) Variability Comments

167.00 71.81 90 greenhouse 

fumigation

plant weight, size, root 

sugar content

No - -

93.00 59.52 90 greenhouse 

fumigation

chlorosis, growth, 

yield

No - -

69.00 27.60 90 greenhouse 

fumigation

chlorosis, growth, 

yield

No - -

120.00 106.80 90 greenhouse 

fumigation

chlorosis, growth, 

yield

No - -

118.00 77.88 90 greenhouse 

fumigation

chlorosis, growth, 

yield

No - -

65.00 26.65 90 greenhouse 

fumigation

59% of leaves with 

chlorsis

Yes - -

45.00 21.15 90 greenhouse 

fumigation

37% of leaves with 

chlorsis

Yes - -

65.00 42.90 90 greenhouse 

fumigation

98% necrosis, 27% 

yield loss

Yes - -

72.00 99.36 90 greenhouse 

fumigation

73% necrosis, 76% 

yield loss

Yes - - Treatment dose far too high relative to known sensitivity of 

gladiolus to HF.

117.00 42.12 90 greenhouse 

fumigation

65% necrosis, 60% 

yield loss

Yes - -

91.00 43.68 90 greenhouse 

fumigation

60% necrosis Yes - -

138.00 60.72 90 greenhouse 

fumigation

48% necrosis, 40% 

yield loss

Yes - -

105.00 73.50 90 greenhouse 

fumigation

59% necrosis, 34% 

yield loss

Yes - -

129.00 64.50 90 greenhouse 

fumigation

62% necrosis, 60% 

yield loss

Yes - -

72.00 29.52 90 greenhouse 

fumigation

36% necrosis, 55% 

yield loss

Yes - -

128.00 143.36 90 greenhouse 

fumigation

necrosis, growth, yield No - -

Note: Scientific Data Used to Derive the Reference Levels is Indicated in Bold Face Type

Science Assessment Document for HF 103 CEPA/FPAC WGAQOG July 1996
Appendix HF Reference Dose Database

Study 

No. Author(s) Year Journal Vol. pg Species Cultivar Life Stage Age

Conc. 

(μg m-3)

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Schupe, H.B Peterson, N.C. 

Leone

105-115 Peach (Prunus) 0.34

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on 

Vegetation, Animals, and Humans" 

ed. J.L. Schupe, H.B Peterson, N.C. 

Leone

105-115 Peach (Prunus sp.) 0.41

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Potato (Solanum 

tuberosum )

growing season 0.44

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Prune (Prunus sp.) 0.89

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Spinach 0.42

19 Hill, A.C., and M.R. Pack 1983 in "Fluorides, Effects on Vegetation, 

Animals, and Humans" ed. J.L. 

Schupe, H.B Peterson, N.C. Leone

105-115 Wheat (Triticum 

aestivum L.)

0.38

20 Murray F., and S. Wilson 1988b Environmental and Experimental 

Botany

28 343-349 Eucalyptus 

(Eucalyptus 

tereticornis)

18 months 0.38

21 Murray F., and S. Wilson 1990 Journal of Experimental Botany 30 215-223 Soybean (Glycine 

max L.)

Dragon 50 days old 0.27

21 Murray F., and S. Wilson 1990 Journal of Experimental Botany 30 215-223 Maize (Zea mays 

L.)

QK 958 54 days old 0.26

21 Murray F., and S. Wilson 1990 Journal of Experimental Botany 30 215-223 Peanut (Arachis 

hypogaea L.)

Virginia Bunch 53 days 

old

0.27

21 Murray F., and S. Wilson 1990 Journal of Experimental Botany 30 215-223 Navy bean 

(Phaseolus vulgaris 

L.)

Gallaroy 26 days old 0.25

Note: Scientific Data Used to Derive the Reference Levels is Indicated in Bold Face Type

Science Assessment Document for HF 104 CEPA/FPAC WGAQOG July 1996
Appendix HF Reference Dose Database

Study 

No.

19

19

19

19

19

19

20

21

21

21

21

Duration 

(days) Dose Dose Period Protocol Endpoint Measured Effect Significant (p<=.05) Variability Comments

110.00 37.40 90 greenhouse 

fumigation

1% necrosis, 73% 

growth

Yes - -

73.00 29.93 90 greenhouse 

fumigation

severe chlorosis, 1% 

necrosis

Yes - -

138.00 60.72 90 greenhouse 

fumigation

necrosis, growth, yield No - -

51.00 45.39 90 greenhouse 

fumigation

necrosis Yes - - No description of results, and no quantitative description of 

necrosis.

38.00 15.96 30 greenhouse 

fumigation

necrosis, growth, yield No - -

88.00 33.44 90 greenhouse 

fumigation

necrosis, growth, yield No - -

90.00 34.20 90 open-top, 

field

specific leaf area (cm2 

g

-1)

Yes 0.01 Eucalyptus is not a Canadian species, nor are there close 

relatives. Therefore this data isn't used in the Ref. Level 

calculation.

91.00 24.57 90 open-top, 

field

Yield No - No sign. effect on yield or yield components.

70.00 18.20 90 open-top, 

field

Yield No - Sign. reduction in no. of immature kernels; no effect on yield or 

any yield component.

105.00 28.35 90 open-top, 

field

Yield Yes 0.001

49.00 12.25 90 open-top, 

field

Yield No - Sign. reduction in avg. bean wt., compensated for by sign. 

increase in number of pods and beans per plant. No net effect on 

yield.

Note: Scientific Data Used to Derive the Reference Levels is Indicated in Bold Face Type

Science Assessment Document for HF 105 CEPA/FPAC WGAQOG July 1996