Introduction
Not surprisingly, there has been more research on the effects of fluoride on humans than on any other animal, so this chapter begins with an account of the sources of flu- oride in the human diet; then it considers the effects of acute and chronic exposures before progressing on to discuss the effects on other mammals and invertebrates.
Humans
In Chapter 2 we saw that, for most animals, ingestion of fluoride in food and drink is the main pathway of uptake. In humans the amount varies greatly from person to person and place to place but in most situations water accounts for half or more of the daily intake. In developed countries and in populations with piped water, the total is typically about 0.2–2.0 mg F/day but fluoridation of public water supplies and consumption of bottled water or carbonated drinks may alter this significantly. In those parts of the world where the fluoride con- tent of drinking-water exceeds 1–2 mg/l, intake is much higher, while in some coun- tries food and tea add a significant burden.
Excessive use of fluoridated toothpaste, gels and mouthwashes may also increase intake significantly. For example, dental products meant to be used topically contain fluoride
concentrations ranging from 250 to over 1500 mg/kg (WHO, 2002a). Workers in industry may be exposed to high concentra- tions in the air and to fluoride-containing dusts, which increases their intake, though industrial exposure is decreasing because of improvements in operating conditions.
Because fluoride occurs naturally in everything we eat and drink, even in pristine environments, it is a normal constituent of human tissues, concentrating in the teeth, bone and any other calcified materials, such as kidney stones. Soft tissues contain around 1 mg F/kg (wet wt basis) and bones and teeth contain a few hundred mg/kg. About 99% of the total body load is retained in the bones and teeth, where it is incorporated into the crystal lattice (WHO, 2002a). Bone is largely composed of a calcium phosphate mineral analogous to crystalline calcium hydroxy- apatite (Ca10(PO4)6(OH)2). Fluoride ions can substitute in the hydroxyl position, altering the solubility and hardness of the tissue.
There appears to be strong evidence that ingestion of fluoride directly stimulates bone and fluorapatite formation in vivo (WHO, 1984, 1994; Grynpas, 1990; Mohr and Kragstrup, 1991; Chavassieux et al., 1993; Ohta et al., 1995; Cao et al., 1996;
Hou, 1997; Ando et al., 1998, 2001). Con- trary to some reports, recent medical and epidemiological evidence suggests that there is no significant relationship between bone strength and fluoride exposure (Sower et al., 1991; Whitford, 1992; Fratzl et al.,
©L.H. Weinstein and A. Davison 2004.Fluorides in the Environment
56 (L.H. Weinstein and A. Davison)
1994; Cauley et al., 1995). At low levels fluoride has beneficial effects in preventing dental caries and it has been used as a treat- ment for osteoporosis for many years. These positive effects have led to an endless debate about whether fluoride is an essential element for humans and livestock (NAS, 1974; WHO, 1984), but it is impossible to test this idea experimentally and the arguments tend to be confounded by emotional con- cerns about the effects of water fluoridation.
It does not seemto be a fruitful topic for discussion here.
Effects of acute exposure
It is difficult to make a clear distinction between acute and chronic effects because the rationale for how an effect is categorized depends upon the concentration of fluoride in the atmosphere, its form (i.e. gaseous or particulate), the length of exposure and sensitivities and tolerances inherent in individual humans. Because workplace exposures in most industries have been shown to be well under allowable threshold limit values (obviously with some excep- tions, depending upon the type of industry, the standards promulgated by individual countries and the degree of enforcement), we assume that normal day-to-day exposures in the aluminium, magnesium, phosphate and other common industries fall within the category of chronic effects.
Even where daily workday exposures have exceeded present-day standards, we consider these to be chronic exposures because no health effects have been registered after a single exposure.
The intense reaction of elemental fluo- rine (F2) with skin produces a thermal burn.
Solutions of HF, on the other hand, produce slow-healing chemical burns (Stokinger, 1949; Hodge and Smith, 1977). The primary treatment for HF burns is the application of calciumor magnesiumsalts, which form insoluble complexes with fluoride, although other traditional burn treatments are also used (Gosselin et al., 1976). Lung tissues are delicate and may be severely
or fatally irritated by high concentrations of F2or HF (Greendyke and Hodge, 1964).
According to Largent (1950) (cited by Hodge and Smith, 1970) the human response to increasing concentrations of gaseous fluoride is as follows:
3 p.p.m. (2.44 mg/m3) – no local immediate systemic effects observed, although some subjects have complained of transient irritation, reddening and itching of exposed skin;
10 p.p.m. (8.13 mg/m3) – many persons undergo discomfort;
30 p.p.m. (24.4 mg/m3) – causes serious complaints and objections;
60 p.p.m. (48.8 mg/m3) – brief exposures result in definite irritation of the conjunc- tiva, nasal passages and discomfort of the trachea and pharynx;
120 p.p.m. (97.6 mg/m3) – the highest concentration tolerated for less than 1 min by two male subjects; smarting of skin also noted.
Most of our knowledge of the effects of acute exposure to fluoride salts comes fromaccidental or deliberate poisoning (Hodge and Smith, 1965), but a detailed discussion of this aspect is beyond the scope of this book. In many of the cases reported in the USA death was due to ingestion of ant or cockroach poison, but there was one tragic case in which sodiumfluoride was unintentionally mixed with scrambled eggs and served to hospital patients: 263 were poisoned and 47 died (Hodge and Smith, 1965). Cases such as this suggest that the acute lethal dose of sodiumfluoride for adults is 5–10 g (32–64 mg/kg body wt) and that the minimum acute dose that might lead to adverse health effects is 5 mg/kg body weight (WHO, 2002a). Generation of hydrofluoric acid affects the gastrointestinal system, causing abdominal pain and other symptoms. Other effects, such as cardiac arrest and damage to the central nervous system, are caused by hypocalcaemia and enzyme inhibition. Normally about 50%
of the total serumcalciumis ionized and it is that formthat is biologically active in bone formation, blood coagulation, functioning of the neuromuscular system and other cellular processes. Fluoride
complexes with calcium and induces hypocalcaemia.
Dental caries
At low concentrations fluoride decreases the incidence of dental caries. The effect has been attributed to three mechanisms:
inhibition of bacterial metabolism; inhibi- tion of demineralization when fluoride is present at the crystal surface during acidifi- cation; and enhancing remineralization by forming a low-solubility veneer, similar to fluorapatite (Featherstone, 2000). Many investigators have credited the major bene- fits of fluoride for anticaries activity to its reactions with tooth mineral, consigning a less important role to its antimicrobial activity. The toothpaste industry promotes the idea that fluoride makes teeth more resistant to acids by issuing protocols for an educational experiment in which eggshells are treated either with water or a fluoride solution and then plunged into vinegar – the fluoride-treated shells are resistant to attack. The mode of action on the human microflora was reviewed recently by Mar- quiset al. (2002). The most direct manner involves the binding of fluoride ions (F−) or HF to sites on enzymes or other proteins, such as the haem moiety of a number of enzymes, including catalases, peroxidases and cytochromes. In intact microbial cells, enolase, a key enzyme of glycolysis, may be inhibited at very low micromolar concen- trations and low pH values. Inhibition of catalase would jeopardize bacteria or mixed bacterial communities in managing with oxidative damage from hydrogen per- oxide. Because organic weak acids, food- preservative weak acids and non-steroidal anti-inflammatory agents have a similar anticariogenic effect to that of fluoride, Marquiset al. (2002) pointed out that:
Fluoride has specific effects on biological systems not shared with organic weak acids, mainly anti-enzyme effects due to fluoride binding or to binding of fluoride–
metal complexes. Fluoride also has effects shared with organic weak acids, mainly those having to do with enhanced transport
of protons across the cell membrane. It is these latter effects that seem to be most pertinent in the antibacterial– anticaries properties of fluoride. Fluoride can even have an anticaries effect when added to sucrose in the diet and can act in concert with other anticaries agents. Moreover, flu- oride appears to have important ecological effects on dental plaque in that it acts to reduce acidification and in the long run serves to select for a less acid-tolerant, less cariogenic microbiota.
The authors go on to say that the antimicrobial–anticaries effects of fluoride relate to ‘reduction in the acid tolerance of glycolysis by intact, cariogenic bacteria in plaque. As a result, acid production is stopped before the plaque pH drops to values leading to rapid demineralization.’
Chronic exposure
Excessive fluoride intake at chronic levels over long periods of time can lead to dental and skeletal fluorosis. The former is charac- terized by failure of the enamel covering the teeth to crystallize properly, resulting in flaws that range from barely discernible white inclusions to severe brown stains, surface pitting, brittleness and excessive wear. Skeletal fluorosis is a slow, progres- sive and crippling affliction. Roholm (1937) produced the first detailed characterization of fluorosis in relation to workers in the cryolite industry. He described how high exposures led to calcification of ligaments, increased mineralization of bone (osteo- sclerosis) and abnormal outgrowths of new bone (exostoses). At its earliest stage, osteo- fluorosis is often asymptomatic but can be visualized radiologically as increasing bone density, particularly of the vertebrae and pelvis. This condition appeared in cryolite workers after about 4 years in which daily absorption of fluoride was 20–80 mg. Over the long term, excess fluoride leads to pain- ful joints and greatly restricted mobility.
In severe cases the person may be permanently bent and may not be able to walk, but less severe forms can be slowly reversible (Grandjean and Thomsen, 1983).
Osteosclerotic changes have been associ- ated with bone fluoride concentrations of about 5000–6000 mg/kg of dry, fat-free bone (Weidmann and Weatherall, 1970; Zipkin et al., 1970; Smith and Hodge, 1979; WHO, 1984). Pathological changes have been found at bone fluoride concentrations as low as 2000 mg/kg (Baud et al., 1978;
Boillatet al., 1979).
Occupational exposure
Since Roholm (1937) published his review there has been a great reduction in indus- trial exposure to fluorides, especially in the developed countries, but even in the 1970s the US National Institute for Occupational Safety and Hygiene (NIOSH) recognized 92 occupations with potential exposure to fluorides and 57 occupations considered to have potential exposures to hydrogen fluo- ride (NIOSH, 1976). The available literature mainly relates to workplace exposures by inhalation or dermal contact in aluminium smelting, magnesium processing, phosphate fertilizer and hydrofluoric acid manufactur- ing and welding operations. The concentra- tion of fluoride in the internal air of workrooms in several industries is shown in Table 3.1. The concentrations vary con- siderably, from a low value of 0.03 mg/m3 to as high as 16.5 mg/m3. These can be
compared with the threshold limit values (TLVs) stipulated by OSHA (2002), which are, for an 8 h day, 5-day week with little or no adverse effects: 0.1 p.p.m. (0.08 mg/m3) for F2 and 3 p.p.m. (2.44 mg/m3) for HF.
The American Conference of Governmental Industrial Hygienists (ACGIH, 1996) pro- posed a ‘ceiling’ value for HF of 3 p.p.m.
but 1 p.p.m. for F2. NIOSH (OSHA, undated) recommends an exposure limit for HF of 2.5 p.p.m. as a time-weighted average for up to a 10-hour working day and a 40-hour working week. The NIOSH short-term exposure limit is 6 p.p.m. Clearly, US government agencies are in relatively close agreement on occupational exposures to HF. There are similar standards in force in other countries but it is interesting that the former USSR recommended a much lower threshold limit value of 1.0 mg/m3expres- sed as HF (US EPA, 1980). The limits indi- cate that humans are remarkably tolerant of atmospheric fluorides, much more so than plants, which is one reason why the authors promote the use of plants for surveillance.
Occupational exposure is generally monitored by analysis of urine, measure- ment of plasma fluoride and radiological examination. Analysis of fluoride in hair has been shown more recently to be a potentially effective method for monitoring (Kokot and Drzewiecki, 2000), but urine analysis is the most widely used technique. About 50% of the fluoride ingested is rapidly excreted in
Industry Country
Concentration of F (mg/m3)
References cited in WHO (2002a) Machine-shops and shipyards
Aluminium smelting Aluminium smelting Aluminium smelting Aluminium smelting Aluminium smelting HF manufacture Phosphate processing
The Netherlands Sweden
British Columbia, Canada Norway
The Netherlands Iran
Mexico Poland
0.03–16.5 c.0.90a c.0.48b c. 0.5b c. 0.5b c.0.93b 1.78cand 0.21c
Up to 3
Sloofet al., 1989 Sloofet al., 1989 Chan-Yeunget al., 1983 Søysethet al., 1995 Sorgdrageret al., 1995 Akbar-Khanzadeh, 1995 Calderonet al., 1995 Czarnowski and
Krechniak, 1990
a34% in gaseous form.
bEither gaseous or particulate fluoride at two smelters.
cDuring 1987–1988 and 1990–1994, respectively.
Table 3.1. Fluoride concentrations in internal workplaces of several industries (data from WHO, 2002a). (Reproduced fromEnvironmental Health Criteria227, Courtesy of WHO, Geneva.)
the urine and the concentration is closely related to the amount ingested and its bioavailability. Dinman et al. (1976) and Hodge and Smith (1977) suggested that no detectable radiological or clinical signs of osteosclerosis will materialize at workplace atmospheric concentrations below 2.5 mg/
m3and at fluoride concentrations in urine that are at or below 4 mg/l preshift (collected at least 48 h after previous occupational exposure) and 8 mg/l postshift over a long time period. These data were the basis for the US recommendations for the threshold limit values established by NIOSH. Because the amount ingested varies, NIOSH (1975, 1976) recognized that a single urine sample was inadequate to assess the general working environment and proposed that, for workers exposed to inorganic fluorides or HF, end-of-shift urine samples should be collected for 4 or more consecutive days. If the fluoride concentration exceeded 7.0 mg F/l, a preshift sample (an estimate of the worker’s skeletal fluoride burden) was to be collected within 2 weeks at the start of a work shift at least 48 h after the previous exposure, and a subsequent postshift sample (an estimate of the exposure conditions during the shift) would be taken at the end of the work week. If the preshift sample exceeded 4.0 mg/l, or the second postshift sample exceeded 7.0 mg/l, the individual’s dietary sources, work practices and environ- mental control were to be evaluated. In the event that the median post-shift urinary fluoride concentrations exceeded 7.0 mg/l, the working environment would undergo an industrial hygiene examination. The efficacy of the 4 mg/l limit is demonstrated by a study by Derryberryet al. (1963). The amount of fluoride excreted in urine at the end of the work shift was measured in 74 workers exposed to high concentrations of fluoride. Unexposed workers were used as the control group. An index of exposure was calculated for each worker based upon the percentage of urine specimens containing
> 4 mg/l. None of the workers were consid- ered to be disabled, although in 23% of the workers minimal or questionable degrees of increased bone density were found, a condi- tion which the authors state would not have
been sufficient to have been recognizable as increased osseous radio-opacity in routine examinations. There were no abnormal findings of gastrointestinal, cardiovascular, metabolic or haematological conditions in the exposed group, although there were more frequent complaints of respiratory conditions.
There have been many epidemiological studies of the health of industrial workers (WHO, 2002a), but, because they are exposed to several potential inciting agents, it is diffi- cult to determine the effects of any single agent unless it causes unique or very specific symptoms. Most reports of skeletal fluorosis have been from aluminium smelters, mag- nesium foundries, fluorspar processing and phosphate fertilizer-processing plants (Table 3.2), but Leoneet al. (1970) stated:
In spite of continual vigilance by industrial health authorities, few cases of human industrial fluorosis have been identified and incidents have mostly been of a trivial character. An exception was in the Danish cryolite industry where cases were identi- fied and investigated by Roholm (1937).
Responses of workers in the aluminium smelting and phosphate fertilizer industries were reviewed by Hodge and Smith (1977) (Table 3.2), but it is important to recall that this was a summary of research that was published from the 1930s to the mid-1970s;
it must not be assumed that similar observa- tions would be made today. Dental fluorosis was rarely a symptom because workers were of adult age, but Hodge and Smith (1977) found a number of consistencies within each industry, such as respiratory problems and skeletal pain. Where there were fluoride effects, air concentrations usually exceeded 2.5 mg F/m3and urinary fluorides were generally equal to or exceeded 9 mg/l. Not surprisingly, there were also many symptoms reported that were unrelated to accepted fluoride effects, including: gastrointestinal and renal com- plaints; headache; eye irritation; vascular dysfunction; cardiac enlargement; men- strual irregularities; and inflammation of the uterus, cervix and vagina. These could have been due to several other pollutants or
be unrelated to the industrial environment.
A number of epidemiological studies have reported increased rates of various cancers in workers in the aluminium industry but the World Health Organization (WHO, 2002a) stated:
In general, there has been no consistent pattern and bone cancer was not usually assessed. Although increases in lung cancer were observed in several studies, it is not possible to attribute these increases to fluo- ride exposureper sedue to concomitant exposure to other substances. Indeed, in some of these epidemiological studies, the increased morbidity and mortality was attributed to the workers’ exposure to aromatic hydrocarbons.
Ambient air near industrial sources Atmospheric fluoride concentrations out- side industrial buildings are usually at least 1000 times lower than inside, so the risk of fluorosis to the population inhabiting the surrounding neighbourhoods would be expected to be minimal. Nevertheless, there have been concerns, especially 30–50 years ago, when emissions were higher and there was less information available. One of the earliest investigations, at Fort William in Scotland, is discussed in Chapter 5 as a case history, but Hodge and Smith (1977) summarized investigations of health near aluminium smelters and phosphate fertilizer factories:
Authors cited in Hodge and Smith (1977)
Air concentration (mg/m3)
Urine (mg F/l)
No. of cases/
no. at risk Aluminium smelting
Kaltreideret al. (1972) Agateet al. (1949) Tourangeau (1944) Visscheret al. (1970) Boillatet al. (1975) Frankeet al. (1972, 1975) Rocheet al. (1960) Lezovic and Arnost (1969) Schlegel (1974)
Coulonb
Roholm (1937); Brunet al. (1941)
2.4–6.4 0.14–3.4 2.5–3.5
– 0.5–3.7
– – – 2–3
– 15–20
9.8
.9a – – – – – 1.15–6a
– 13 postshift Average 16
76/79
‘A few’
2/10 9/17 18/20 28/?
1/?
,4/50, 2 slight, 2 mod.
61/?
13/631 57/68 Other industries
Largentet al. (1951)
Peperkorn and Kehling (1944) Dale and McCauley (1948) McGarvey and Ernstene (1947) Henderson (1975)
Wilkie (1940)
Derryberryet al. (1963) Bowleret al. (1947) Fritz (1958) Bishop (1936)
Fourrier and Champiex (1956)
1.2–3.9 – – – 0.06–8.2
– 3.4 0.1–0.7
– – –
> 10c . – 10.8 23.8 2–6 preshift 4–25 postshift
15.8 0.5–44 average 4.7
0.5–7.5 – – –
5/16 34/47 24/40 1 1/4
2 17/74
1/54 67/156
1 4
amg/24 h urine.
bPersonal communication to Hodge and Smith.
cIn 4/5 with severe osteosclerosis.
Table 3.2. Occurrence of industrial osteosclerosis in various industries (from Hodge and Smith, 1977).
(Reprinted courtesy of ACOEM.)