Fluorine

Chapter 14

Fluorine I. INTRODUCTION

Fluorine (F) is a very toxic element: fluorosis is found in many parts of the world. Fluoride in small amounts is beneficial for dental health and may be useful in the treatment of osteoporosis. Only toxicity consideration of F appears to be of importance to livestock. Excellent reviews on the importance of F in animal and human nutrition are available (NRC, 1971, 1974; Krishnamachari, 1987; Phipps, 1996; Cerklewski, 1997). The terms fluorine and fluoride and the symbol F will be used interchangeably in this chapter.

II. mSTORY Biological interest in F was first confined to toxic effects of the mineral. Fluoride toxicosis in grazing livestock was observed about the year 1000 in Iceland, where it was associated with volcanic eruptions (Roholm, 1937). The disease caused domestic animals to turn sick and die when they consumed grass contaminated with the fallen ash. The clinical signs disappeared when the animals were taken indoors and fed on hay produced before the eruption. In many areas along the coastal plains of North Africa, animals and man have been troubled for centuries by a serious, often painful, deterioration of the teeth and bones called darmous that eventually was found to be caused by excessive F ingestion (NRC, 1974). Fluorine, crudely prepared by Scheele in 1771 and named in 1812 by Ampere, was not actually isolated until 1886 by Moissan (Cerklewski, 1997). By 1831, chronic endemic fluorosis in humans and livestock was further established in several parts of the world (NRC, 1980). Fluoride-bearing fumes and dusts from industrial plants processing F-containing raw minerals, such as bauxite or phosphate rock, were found to constitute a health hazard to animals and man living nearby (Roholm, 1937). In the 1920s, the use of phosphorus (P) supplements containing excessive F increased the toxicosis in animals. Beneficial effects of F in human health were reported by Dean (1942), who established a correlation between the F concentration of drinking water and community prevalence of dental caries. Even earlier, Erhardt (1874) recommended that children during the second dentition, take F pastilles. 449

Fluorine

450

III. CHEMICAL PROPERTIES AND DISTRIBUTION

Fluorine is a highly reactive nonmetal1ic, pale yellow gaseous member of the halogen chemical group, with a molecular weight of 18.99. It is the most electronegative of all elements and can react vigorously with most oxidizable substances at room temperature, frequently with ignition. Fluorine does not occur in the elemental state in nature, but exists as the monovalent anion fluoride (F-). Fluorine combines directly or indirectly, to form fluorides with all the elements except helium, neon, and argon. Fluorine, chemical1y bound as fluoride, is found both in igneous and sedimentary rock. Fluorine is widely distributed in the earth's crust and constitutes approximately 0.06 to 0.09% by weight of the upper layers of the lithosphere. The primary F-containing minerals are fluorspar (CaF 2) , cryolite (Na3AlF6), and fluorapatite (Ca,oF 2(P04)6). An example of extensive deposits of phosphate rock consisting chiefly of fluorapatite is a 500-mile2 area at Bartow, Florida (USA). The F content of soils varies greatly from one location to another, owing mainly to differences in geological origin of the soils and to fertilization practices. Most plant species have a limited capacity to absorb F from soil. Natural forages are characteristical1y low and normally contain 2 to 20 ppm F on a dry weight basis. There is ample evidence that no consistent relationship exists between total F in soil and in plants (NRC, 1974). The major source of F for humans is water, whereas livestock can receive toxic quantities of the element through contaminated plant materials and phosphate supplements, in addition to high-F water concentrations (see Section VI). Of feeds of animal origin, only bones may contain substantial concentrations of F, while soft tissues and fluids rarely contain more than 2 to 4 ppm (Underwood and Suttle, 1999). The adult human contains 3 to 7 mg of F. IV. METABOLISM

A. Absorption Soluble F, even at high dietary concentrations, is rapidly and almost completely absorbed by passive absorption from the gastrointestinal tract. Observations from humans, rats, and domestic animals have shown F absorption from the stomach and the rumen in ruminants (NRC, 1980; Nopakun et al., 1989). The half-time for absorption is about 30 minutes, so peak plasma concentration usual1y occurs within 30 to 60 minutes. Most ingested F is absorbed from the upper intestines. In the stomach, F uptake depends on the formation of hydrogen fluoride prior to its assimilation into the blood as the F ion. Under conditions of higher gastric acidity in the stomach, F absorption is promoted, whereas alkalinity impairs uptake. Absorption of F is variable depending to a large part on the solubility of that ingested (see Section VI). Poorer absorption, ranging from 37 to 54% has been reported for the F from bone meal. The F in fish protein concentrate has also been

Metabolism

451

reported to be only 42 to 52% as available to young rats as sodium fluoride (Zipkin et al., 1969). Best estimates of F absorption in human diets are 50 to 80% (Singer and Ophaug, 1984). Fluoride absorption can be affected by other dietary minerals, protein, and fats; absorption is reduced by aluminum (AI), calcium (Ca), magnesium (Mg), and boron (B), while fats increase absorption (Cerklewski, 1997). Supplemental B reduced the absorption of F by increasing its fecal excretion (Vashishtha et al., 1997). At least part of this reduction in F absorption from the diet is caused by insoluble complex formation with cations in the alkaline small intestine, predominately with Ca and Mg (Cerklewski, 1997). Protein may favor F absorption by stimulating gastric acidity and fat by delaying gastric emptying time.

B. Tissue Concentrations, Storage, and Excretion Ingested F is rapidly absorbed and transferred into the blood, where it reacts almost instantaneously with Ca to form calcium fluoride. In that form, F makes its way into the hard tissues, displaces surface anions, and in due course, enters the bone crystal lattice (Krishnamachari, 1987). The plasma F content is maintained within narrow limits by regulatory mechanisms that involve principally the skeletal and renal tissues. The primary pathway of F excretion is urine ("-'90%). In fact, urinary excretion increases with intake and remains elevated as long as the content in the bone is excessive, thus providing a mechanism for reducing body F with time. The dog kidney can concentrate plasma F in urine by a factor of 10 to 20 times (Carlson et al., 1960) through glomerular filtration and variable tubular resorption. Approximately half of F absorbed by humans is excreted in the urine; the remainder is stored primarily in bone. Loss of F in sweat is considered to be negligible except with profuse sweating. Renal clearance of F is linear with glomerular filtration rate with about 60% of filtered F being reabsorbed (Cerklewski, 1997). Skeletal F accumulation can increase, within limits, over time without morphological evidence of pathology. However, in cases of high F intake, structural bone changes develop. Typically about 99% of the total F in the body is in close association with Ca in the skeleton and teeth, where it exists as the inorganic mineral fluorapatite (NRC, 1974). For teeth, maximum F deposition occurs during childhood and, unlike bone, it is not subject to resorption because of the severed blood supply following tooth eruption (DePaola et al., 1994). The ability of F to enter the hard tissues has been ascribed to its capacity to replace other anions on the bone crystal lattice such as hydroxide (OH-) and citrate ions. Once the F ion is incorporated in the apatite of bone, it cannot be removed without resorption of the unit crystalline structure of the mineral phase. Although it is well established that the F content of bone gradually decreases after withdrawal from the exposure, Dominok et al. (1984) were able to demonstrate significantly elevated F concentrations in bone as late as 21 years after cessation of exposure. Most soft tissues and fluids do not accumulate much F, even during high intakes, although tendon, aorta, and placenta have higher concentrations than other soft tissue, possibly associated with their relatively high levels of Ca and Mg

452

Fluorine

(NRC, 1980; Phipps, 1996). Kidney will usually exhibit a high F concentration during high-F ingestion, because of urine retained in the tubules and collecting ducts. Milk F concentrations can be affected by diet F (Sarna1and Naik, 1995) and the element can cross the placental F barrier. Exposure of pregnant and lactating animals to F raises blood F concentrations of the neonate and the milk of the dam, but the increases are far less than those seen in the dam's bloodstream. The impact of placental transfer may be modified by the rapidity with which absorbed F is excreted in the urine and deposited in the bone. Birds consuming high-F diets can readily transfer F to the egg, especially into the yolk. Nutrient deficiencies influence the placental F barrier. Cerklewski and Ridlington (1987) reported that maternal Mg deficiency in rats significantly increased femur and first molar F concentrations in the offspring. Placental transfer of F in rabbits induced congenital fluorosis in the young (Santos et al., 1996). Hobbs and Merriman (1962) fed 108 ppm F, as sodium fluoride (NaF), to cows, and it appeared that neither placental F transfer nor milk F concentrations were sufficient to adversely affect the health of these calves.

V. FUNCTION AND ESSENTIALITY The F ion has a high affinity for incorporation into bone and teeth. In infants, retention of a F dose ranged from 75 to 87% (Ekstrand et aI., 1994). This retention is higher than that seen in adults and may indicate that the infant has a greater capacity to deposit fluoride in bone (Hunt and Stoecker, 1996). Fluoride's high degree of reactivity (electronegativity) and its small ionic radius allows F either to displace the larger hydroxyl ion in the apatite crystal, forming fluorapatite, or to enter spaces between the hydroxyapatite crystal, thereby increasing crystal density (Cerklewski, 1997). A reaction equation to describe the displacement of the hydroxyl ion by F in the apatite crystal is:

An additional benefit to teeth is that F can inhibit the growth of acid-producing dental plaque bacteria (Maltz and Emilson, 1982). Also, F is known to have both stimulatory and inhibitory effects on many tissue enzymes; however, the physiologic significance is doubtful as large levels are required (Kirk, 1991). A clear-cut F deficiency has not been observed in animals under natural conditions. Schwarz and Milne (1972), working in a filtered-air environment, reported a favorable growth response when small increments (1 to 2 ppm) of F were added to a low-F diet for rats. However, Doberanz et al. (1963) fed a diet containing less than 0.005 ppm and found no difference in general health or growth rate between rats fed this diet and rats fed the same diet plus 2 ppm F in their drinking water. A similar study (Weber, 1966)failed to find that F was essential for mice raised through three generations. However, Messer et al. (1973) have reported that mice fed diets containing low levels of F (0.1 to 0.3 ppm) developed anemia,

Function and Essentiality

453

and reproduction was impaired. Tao and Suttie (1976), using the same low-F diet fed to mice by Messer et al. (1973), found no impairment of reproduction, and suggested that the apparent essentiality of F proposed by Messer and associates was the result of a pharmacological effect of F in improving iron (Fe) utilization in mice fed a diet marginally sufficient in Fe. Whether F is considered essential depends on the criteria used. Until recently, no one had produced an environment so low in this element that animal survival has been vitally threatened. The only evidence of essentiality of F in farm animals comes from a study by Anke et al. (1997), who reported skeletal abnormalities in female goats and poor growth in their offspring after ten generations on a diet containing <0.3 mg/kg OM. In poultry, 80 ppm F served as a growth factor in broiler diets (Gutierrez et al., 1993). For humans, F was once considered an essential nutrient, mainly on the basis of reducing the prevalence and severity of dental caries in both children and adults. However, the Food and Nutrition Board of the National Research Council withdrew the term "essential" because the essential role for F could not be confirmed. A viewpoint is that nutritional requirements should include consideration of the total health effect of nutrients, not just their roles in preventing deficiency pathology (Nielsen, 1996). Therefore for F, the terms "beneficial element" and "apparent beneficial intake (ABI)" are in use. For humans, the ABI for maximal benefit against dental caries is suggested to be 0.05 to 0.07 mg/kg body weight (Burt, 1992). It has been definitely shown by both epidemiological and experimental studies that where the water supply contains I to 2 ppm, the incidence ofdental caries is decreased during the period of tooth development (Mandel, 1979). Decay can be reduced 50% or more in young children; the effect is permanent so long as the individual continues to ingest an adequate amount of the element. The effectiveness of fluoridation in reducing dental decay was recently reemphasized by the observation that among 9-year-old children, the prevalence of dental caries declined from 71% during 1971 to 1974 to 34% during 1985 to 1986 (NCHS, 1992). Lifetime benefits of F are greatest when individuals are exposed to F during both the preeruptive and the posteruptive life of the tooth (Grembowski et al., 1992). Dental caries do not present a health problem in farm animals, as it does in humans. Evidence has accumulated that, in humans, the optimal F intake in early life may provide some protection against excessive demineralization of bone (osteoporosis) in aged individuals and atherosclerotic calcification (Bernstein et al., 1966). Arnold et al. (1997) reported the effect of long-term exposure to fluoridated water from growth to young adulthood on bone mineral density and found a positive impact on axial spine bone density. Sodium fluoride as a therapeutic agent stimulates bone formation and may be effective in preventing osteoporotic fractures. It may be an acceptable alternative treatment to estrogen or bisphosphonate therapy and useful in premenopausal and corticosteroid-induced osteoporosis and in some patients with mild osteogenesis imperfecta (Murray and Ste-Marie, 1996). Low-dose F given continuously with Ca for prolonged periods can decrease vertebral fracture rates compared to Ca alone in patients with mild to moderate osteoporosis (Reginster et al., 1998).

454

Fluorine

Fluoride supplementation of individuals at 15 to 50 mg NaF/day has been shown to promote the formation of new bone in the axial skeleton, especially in the lumber spine (Kleerekoper and Balena, 1991; Chavassieux and Meunier, 1995; Farrerons et al., 1997).Calcium supplementation, usually at 1000 mg, must accompany F to see increased osteoid surface, increased osteoid thickness and volume, and thickening of existing trabeculae. In only two months, positive effects can be seen in persons suffering from bone loss (Cerklewski, 1997).

VI. SOURCES

Chronic fluorosis in grazing livestock generally results from three sources: (I) continuous consumption of high-F P supplement, (2) drinking water high in F (3 to 15 ppm or more), and (3) grazing F-contaminated forages adjacent to industrial plants that emit F fumes or dust. With notable exceptions, the F content of plants is seldom more than 1 to 4 ppm, since most plants have a limited capacity to absorb this element. However, highly toxic concentrations, mainly as fluoracetate, have been reported in several South African plants (Marais, 1943). Toxicosis of F for grazing ruminants in the form of fluoracetate is reported in the following plants: Dichapetalum cymosum, Acacia georginae, Palicourea marcqravii, Gastgrolobium spp. and Oxylobium spp. The tea plant and camellia are also high in F, containing 100 ppm or more of the element (Underwood, 1977). According to the NRC (1974), F content of vegetation will be dependent on the following: (1) the amount and kind (particulate or gaseous) of F escaping into the atmosphere, (2) the distance of the vegetation from the source of contamination, (3) the type and kind of vegetation and its growth rate, (4) duration of exposure, and (5) distribution patterns as affected by wind and topography. The concentration of F in 107 samples of alfalfa hay from areas throughout the United States, believed to be free from industrial F contamination, ranged widely from 0.8 to 36.5 ppm, with a mean of 3.6 and a median of 2 ppm (Suttie, 1969). Fluorine levels for grasses grown in Florida (USA) averaged 2.9 ppm F for nine samples of stargrass (Cynodon nlemfuensis) and 3.47 ppm for seven samples of bahiagrass (Paspalum notatum) (Ammerman and Henry, 1983). Although uncontaminated forages are generally low in F, plants may be very high in the element when contaminated by deposition of fumes and dusts of industrial origin. Phillips et al. (1955) noted that forages grown in areas not subjected to industrial contamination will contain from 2 to 75 ppm F, whereas those grown in areas where F is emitted into the atmosphere may contain from 500 to 1000 ppm. Mining for lead (Pb), and more recently fluorspar, in the Peak District area of Derbyshire, UK, has resulted in extensive contamination of agricultural land with Pb, zinc (Zn), and F (Geeson et al., 1998). From India, F intoxication occurred in cattle in the vicinity of an aluminum smelter (Swamp et al., 1998). Overall incidence of disease was 42.3%, the highest incidence was 58.3% and that was within three kilometers of the smelter with the condition declining exponentially with the distance from the smelter.

Sources

455

Fig. 14.1 Cow with exostosis (Bony growth) of the bones caused by ingesting large amounts of fluorine in Polk County, Florida. (Courtesy of R.L. Shirley, University of Florida, Gainesville)

Industries that have been incriminated in F toxicosis problems include phosphate ore processors; AI, steel, and copper smelters; some chemical manufacturers; brick or ceramic product factories; and coal-fired electricity generating plants. Figure 14.1 illustrates F toxicosis in a cow grazing forage near where phosphate ore is processed. Industrial contamination of forages is much less in recent years for many countries because technology for removing toxic substances from industrial effluents has been vastly improved. A survey of fluorosis was conducted in villages near a fluorspar processing plant near Bombay, India. A resurvey 12 years later indicated that the industry has reduced F air pollution by 90 to 96% during the interim period (Desai et al., 1993). Not all forages contaminated by above normal levels ofF are the result of industry. Although instances are rare, certain crops grown in high-F soils in nonindustrial areas have been found to be so contaminated with soil blown or splashed onto the vegetation that they contain as much as 300 ppm F on a DM basis (Merriman and Hobbs, 1962). The ingestion of soil F by animals grazing forage too closely is also of considerable importance. In the normal feeding of animals, primary sources of dietary F are the mineral supplements and related feed ingredients. The inorganic phosphates used to provide supplementary dietary P are generally considered the major potential source of Fin the diets of most domestic animals. The majority of domestic feed phosphates originate from rock phosphate deposits having F levels ranging from 2 to 5% F and averaging approximately 3.5% (Van Wazer, 1961). Continental sources of rock phosphate generally contain 3 to 4%, whereas the Pacific and Indian Ocean island

Fluorine

456

TABLE 14.1 Typical Fluoride and Phosphorus Content in Phosphorus Supplements"

Compound"

Fluorine contribution from compound to provide 0.25% phosphorus (ppm)

Fluorine (%)

Phosphorus (%)

P:F ratio

0.16 0.14 0.16 0.18 0.16 0.12 0.18

21.0 18.5 18.0 24.0 20.0 14.5 23.7

131 132 113 133 125 121 132

19 19 22 19 20 20 19

0.03 0.05 0.05 0.03 0.03 0.03 0.02 0.03

23.0 18.5 19.5 25.5 21.5 25.0 16.0 23.7

767 370 390 850 717 833 800 790

3 7 6 3 4 3 3 3

1.2 3.7 0.45

9.0 13.0 14.0

7.5 3.5 31

334 710 81

2.0 2.0

21.0 20.0

10.5 10

238 250

2.5

23.7

9.5

264

Defluorinated phosphates manufactured from defluorinated phosphoric acid Monocalcium phosphate Dicalcium phosphate Defluorinated phosphate Monoammonium phosphate Diammonium phosphate Ammonium polyphosphate solution Defluorinated wet-process phosphoric acid Defluorinated phosphates manufactured from furnace phosphoric acid Monocalcium phosphate Dicalcium phosphate Tricalcium phosphate Monosodium phosphate Disodium phosphate Sodium tripolyphosphate Ammonium polyphosphate solution Feed-grade phosphoric acid High-fluoride phosphates Soft rock phosphate Ground rock phosphate Ground low-fluorine rock phosphate Triple superphosphate Diammonium phosphate (fertilizer grade) Wet-process phosphoric acid (underfluorinated)

"Adapted from NRC (1974). b A defluorinated phosphate compound must contain no more than one part fluorine to 100 parts phosphorus (AAFCO. 1973).

deposits usually contain only about half that concentration. Table 14.1 lists the typical F content of phosphate sources in relation to P content. Fluoride is removed to a large extent from most commercial, feed-grade phosphates. A phosphate compound, to be classified as defluorinated, must contain no more than one part ofF to 100parts P(AAFCO, 1973).In the United States, more than 97% of the phosphates being used have been chemically processed to remove F;

Sources

457

dicalcium-monocalcium phosphate mixtures and defluorinated phosphates are the major sources (Ammerman and Henry, 1983). However, in a number ofcountries (e.g., developing countries) often fertilizer and raw rock phosphates are used in situations of unavailability of economical feed-grade phosphates. Fluoride-containing rocks constitute a primary source of environmental F, which leaches out from time to time into the soil and hence into subsoil water. The F present in the water may be in the form of one of the salts of sodium or potassium (Krishnamachari, 1987). Fluorine levels in water vary tremendously from one geographical location to another. The F content of natural waters depends on such factors as the source of water (surface or subterranean), type of geologic formation present, amount of rainfall, and amount of water lost by evaporation (NRC, 1974). Volcanic eruptions (Araya et al., 1993) and geothermal waters often contain large quantities ofF. From a volcanic eruption in Chile in 1988,Arayaet al. (1993) reported that levels of F in forage were dangerous for livestock for at least two years after cessation of the eruption. Water high in F (3 to 15 ppm or more) is usually from deep wells originating from deep rock formations rather than from surface water supplies. Excessively high levels of F in water supplies can also occur from contamination. A level of two ppm F has been indicated by the U.S. National Academy of Sciences (NRC, 1974) as the recommended upper limit of F concentration in water for livestock and poultry. Although dental fluorosis occurs with 2 ppm soluble F in drinking water, serious toxicosis problems are generally not observed unless the element is present at levelsof 5 ppm or more (Harvey, 1952). However, mottled teeth have been observed in cows drinking water that contains 4 to 5 ppm of the element. The grain portion of plants and their by-products usually contain only 1 to 3 ppm F (Underwood and Suttle, 1999). Feeds of animal origin, other than those containing bone, are low in F because the soft tissues and fluids of the body rarely contain more than 2 to 4 ppm on a dry basis. Milk and milk products have even less. Fresh cow's milk contains 0.1 to 0.3 ppm F or 1 to 2 ppm of the dried solids. Animal by-products containing bone may contribute significant quantities of F to animal diets, depending on the amount of by-product used (and bone contained) and the dietary history of the animals from which the by-products were derived. Bone ash normally contains less than 1500 ppm of F. However, cattle grazing F-contaminated pastures can have bone ash containing over 10,000 ppm or 5.5 parts of F for each 100 parts of P (NRC, 1980). Bone meal can constitute a considerable source of F to livestock, whereas meat meal or tankage is a significant source only when it contains a high proportion of bone. Bones of mature animals, even in the absence of abnormal exposure to F, are very much higher in F than are the bones of young animals, as F accumulates in bone during the aging process. The degree to which F is utilized by the animal depends on its source or chemical form. Fluorine in the forms of calcium fluoride (CaF 2) and raw rock phosphate were reported to be 50% as available as F from NaF (Clay and Suttie, 1981). Soluble fluorides, such as NaF, are almost completely absorbed from the gastrointestinal tract, whereas the F of less soluble or more slowly soluble compounds, such as bone meal, CaFb rock phosphate, and defluorinated rock phosphate, are less well absorbed, probably only to the extent of one-third to two-thirds of the F present.

458

Fluorine

Shupe et al. (1962) presented data that F in hay is as available as that in NaF. Biological availability of water F is influenced by total alkalinity, the amount of Ca and Mg salts present, and total hardness. In general, however, F in gaseous, particulate, or dissolved form is readily available to humans and animals (Krishnarnachari, 1987). Godoy and Chicco (1997) found F more available from triple superphosphate than two rock phosphate sources. Sheep bone F concentrations averaged 19% lower for the rock phosphate sources. All of these sources were 26.1 to 33.6% lower than the more available F from dicalcium phosphate. For humans, the principal natural source of F poisoning is from water high in F. Tea and some fish sources can provide high levels of F to some populations. Tea plants are rich in F and the highest levels are found in older leaves which are used to make brick tea. It was concluded that brick tea was the major source of F intake by the Tibetan population (Cao et al., 1996). The prevalence of dental fluorosis of children 8 to 15 years of age from four nationalities in Sichuan and Gansu providences in China ranged from 51.2 to 84.4% (Cao et al., 1997). The greatest factor related to fluorosis was the large consumption of brick tea. The higher content of F in seafood vs freshwater fish is related to the fact that seawater contains twice the level of F (Cerklewski, 1997). Nevertheless, Mwaniki and Gikunju (1995) reported high tissue levels of F in fish from Kenyan fresh water lakes. Consumption of large amounts of these milled fish in enriched formula among infants, toddlers, and young children, would significantly raise the risk of developing dental fluorosis.

VIII, TOXICITY

A. Effects of Toxicity Target-specific effects of excess F have been described. Secondary and tertiary hyperparathyroidism have been described in humans and animals exposed to excess F, which also induced calcification of soft tissues, such as ligaments, tendons, membranes, and periarticular attachments (WHO, 1996). In toxic amounts, F interferes with Ca metabolism; increases bone accretion rate, increases bone resorption rate, and increases total body turnover of Ca (WHO, 1996; Raffi et al., 1997; Borke and Whitford, 1999). Low Ca intakes can result in increased F uptake (Dunipace el al., 1998). Teotia and Teotia (1994) reported that dental caries were caused by high F and low dietary Ca intakes, separately and through their interactions. Dental caries were most severe and complex in Ca-deficient children exposed to high intakes of endemic F in drinking water. Fluoride in excess also interferes with collagen synthesis in bone (WHO, 1996). In laboratory animals, toxic amounts of F have been shown to reduce 14C-labeled proline incorporation into the hydroxyproline of bone collagen. A significant but less critical affect of F toxicosis is the ruminal decrease in volatile fatty acids and protozoal population (Kapoor et al., 2002).

Toxicity

459

Chronic fluorosis is endemic in sheep, cattle, goats, horses, and man in parts of India, Australia, Turkey, Africa, and other world regions as a consequence of the consumption of waters abnormally high in F (McDowell, 1985; Ergun et al., 1987; Underwood and Suttle, 1999). Acute F toxicosis is relatively rare and has most frequently resulted from accidental ingestion of high levels of such F compounds as sodium fluorosilicate used as a rodenticide and NaF used as an ascaricide in swine (NRC, 1974). The following signs and changes are usually observed: high F content in blood and urine, restlessness, stiffness, anorexia, reduced milk production, excessive salivation, nausea, vomiting, incontinence of urine and feces, clonic convulsions, necrosis of mucosa of digestive tract, weakness, severe depression, and cardiac failure. The major clinical signs of F toxicosis are found in teeth and bone. Mottling of the developing teeth is the first sign of fluorosis and is also the most sensitive reaction to F. If animals are young, the teeth may become modified in shape, size, and color. The incisors may become pitted, and the molars may show cavities due to fracture and wear, especially if excess F has been consumed before development of the permanent teeth. Jaw and long bones develop exostosis (Fig. 14.1), and joints may become thickened, causing the animal to become stiff and lame. Abnormalities caused by F ingestion occur only in those teeth that are in the formative stage at the time of exposure (Suttie and Phillips, 1960), so it may not appear immediately. Therefore, animals may show signs of F toxicosis at a later time when they are consuming low-F diets. Fluorine is not equally toxic to all species of animals. Table 14.2 contains suggested F tolerances for different animal species (Thompson, 1978). The animals exhibiting the greatest tolerance to fluorosis are poultry, followed by swine, horses, sheep, and cattle. Young animals are most affected by fluorosis. Livestock are protected against fluorosis by increased urinary F excretion and by skeletal tissue deposition. Nevertheless, F is a cumulative poison, and once bone tissue is saturated, continued intakes are deposited in soft tissues, with the result of metabolic disturbances and death. 1.

RUMINANTS

Ruminants are more susceptible to F toxicosis than are nonruminants. Most of the experimental work on F has involved cattle, but a number of studies have utilized sheep. Sheep being raised for lamb or wool production can tolerate 60 ppm F in their diet, and finishing lambs can tolerate up to 150 ppm F with no effect on growth rate. For cattle, a level of 20 to 30 ppm of total F in the diet will cause dental mottling; above 50 ppm, F will cause a significant incidence of lameness and decreased milk production in lactating cows. Cattle frequently have decreased feed intake when dietary F is greater than 50 ppm. Data from heifers 5 to 6 months of age suggested that these animals can be fed up to 50 ppm of a soluble F in their diet with no adverse effect (Clay and Suttie, 1981). Long-term experiments with beef cattle indicate that 30 ppm of dietary F results in excessive wearing and staining of teeth (Hobbs and Merriman, 1962). Suttie et al. (1957),

Fluorine

460

TABLE 14.2 Suggested Fluorine Tolerances for Animals··b Animal Breeding animals Beef or dairy calves" Beef or dairy heifers" Mature beef dairy cattle" Ewes Horses Sows Laying hens Animals to be slaughtered Beef or dairy calves" Beef or dairy heifersd Growing chickens (broilers) Mature beef dairy cows" Feeder lambs Finishing pigs

Tolerance level (NRC, 1980) (F ppm in diet)

Definitely unsafe (F ppm in diet)

30--40 40-50 60 40-60 100-150 400

40 and 50 and 60 and 70 and 80 and 160 and 440 and

above above above above above above above

35 50 300 100 150 150

65 and 80 and 340 and 120 and 170 and 200 and

above above above above above above

'Modified from Thompson (1978). "These levels are based on the assumption that the animals receive an otherwise adequate diet. The values presented assume the ingestion of soluble fluoride, such as NaF. When the fluoride in the diet is present in the form of dicalcium phosphate, these tolerances are increased by approximately 50%. 'Calves up to 4 months of age. dHeifers 4 months to 2 years of age. 'Cattle 3 years of age or older.

observed that lactating cows could tolerate 30 ppm with no apparent difficulty, that 40 ppm was a marginal tolerance, and that 50 ppm would result in fluorosis within 3 to 5 years. Figures 14.2 and 14,3 show teeth and metatarsal bones of cattle and sheep suffering from fluorosis. Clinical signs of fluorosis from a dairy herd in Bombay, India included the hind limb lameness, reluctance to move, skeletal deformities, bony exostoses, and wasting of the hind quarters and shoulder muscles. Slight to marked dental lesions, loss in milk production, intermittent diarrhea, and emaciation were also present (Singh et al., 1995). Chronic toxicosis caused lameness, dental lesions, and ill thrift in an extensive beef cattle herd in northern Australia (Jubb et al., 1993). Up to 15% of the herd was lame and the disease forced the culling of large numbers of cows. The source of F was fertilizer grade monoammonium and diammonium phosphate fed as part of a mineral supplement. Large quantities of mineral supplement were provided to the cattle because lameness was attributed to P deficiency, which is endemic in the area. Most lameness developed in the late dry season in the post-lactation phase. Severe lameness was caused by fractured pedal bones. Cattle in tropical countries that are provided with inadequate supplies of energy and protein during extended dry seasons are particularly susceptible to F toxicity. General undernutrition apparently enhances the deleterious effects of F toxicosis

Toxicity

461

Fig. 14.2 Fluorosis in cattle. A - incisors from 4-year-old bovine with severe dental fluorosis. Lesions include enamel hypoplasia, hypocalcification, staining, and abnormal wear and reflect a nearly constant elevated fluoride intake during the period of tooth formation. B - incisors from 5-year-old bovine with severe dental fluorosis reflect intermittent periods of elevated fluoride ingestion during the period of tooth formation. C -lower photo shows normal bovine metatarsal. Upper photo shows severe periosteal hyperostosis and roughened irregular surface consisting of disorganized and poorly mineralized bone. Note that the articulating surfaces are unaffected. (Courtesy of J.L. Shupe and A.E. Olson. Utah State University, Logan)

(Suttie and Faltin, 1973). Younger sheep and sheep in a relatively poor body condition were more affected with fluorosis than older sheep and those in a relatively better condition (Schultheiss and Van Niekerk, 1994). For cattle, the developing incisors are sensitive to F from the ages of a few months to about 30 months. Thus, animals not exposed to F until they are 2.5 to 3 years old will not show the typical F-induced lesions. Exostoses of the jaw and long bones develop in ruminants of any age, and the joints become thickened and ankylosed.

462

Fluorine

Fig. 14.3 Right maxilla in lingual view of sheep from eastern part of Turkey. As a result of fluoride toxicosis, the maxillary M) was ankylosed with its eruption interrupted and mandibular M) showed a corresponding extrusion. Staining is illustrated with all teeth abraded and the edges sharp. (Courtesy of H.S. Ergun, Ankara University, Turkey)

Stiffness and lameness (Fig. 14.4) then become apparent, and movement is difficult and painful. Growth may be subnormal, and weight losses may occur, together with a reduction in fertility and milk production. The impairment of these processes is mostly, but not entirely, secondary to the reduced feed intake brought about by the dental lesions and joint abnormalities and the consequent inability and unwillingness of the animal to graze and masticate forage. Poor calf and lamb crops characteristic of fluorosis areas arise primarily from mortality of the newborn due to the impoverished condition of the mothers, rather than from a failure of the reproductive process itself (Harvey, 1952). Mottled teeth have been observed in cows drinking water that contained 4 to 5 ppm of the element. Sheep consuming water with 20 ppm F for 2 to 3 years were not adversely affected with regard to food consumption, dental development, or wool production, but young sheep <1 year of age developed mottling of the teeth from drinking water with 2:5 ppm F (Pierce, 1959). Indian breeds of sheep were able to tolerate 20 ppm F in water for 4 years (Mittal et al., 1994). However, sheep which received higher water F (30 and 40 ppm) in year four had clinical signs that included lameness and emaciation in about 50%, and mottling and staining of teeth in 60 to 70% of treated sheep. In total intake calculations, the F present in water should be taken into account. Kierdorf and Kierdorf (2000) compared dental fluorosis of two species of deer. Differences were found and were related to different timing of crown formation of teeth. Red deer (Cervus elaphus) were found to be highly sensitive bioindicators of environmental pollution by F (Kierdorf et al., 1996).

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Fig. 14.4 Severely lame 7-year-old Holstein cow due to excessive fluorine intake. The cow also had severe bone lesions. (Courtesy of J.L. Shupe and A.E. Olson. Utah State University, Logan)

2.

HORSES

Several workers have noted that affected horses are found in the same geographical areas in which cattle have been injured by industrial effluents (Shupe and Olson, 1971; Cunha, 1990). From analysis of pastures affected by industrial F effluents, Shupe (1972) suggests that 60 ppm F is the tolerance level for horses. Horses with moderate to marked fluorosis appeared unthrifty (Fig. 14.5) even when they had an ample supply of good-quality feed. The hair coat was rough and dry in appearance, and the skin was taut and less pliable than normal. When tooth abrasion and wear become excessive, feed utilization is poor and "slobbering" of poorly masticated feed becomes common. As the toxicosis increases, the horses develop marked clinical fluorosis, they become lame and are unable to walk, run, or jump normally. Horses exhibit apparent pain and often stand with their feet in unnatural positions with one forefoot placed in front of the other. Moreover, the horses shift the position of their feet frequently as if they were trying to relieve the pain. As with other species, fluorosis in horses results in excessive teeth wear and abrasion. Irregular and uneven teeth result in poor chewing with injury to the surface of the cheek and gum. As the teeth become more affected, some of the teeth break down and allow feed material to be forced through the holes in the teeth and into the pulp cavity. This material will form abscesses causing a lumpy jaw appearance (Fig. 14.5). The bones appear chalky white with a rough, irregular surface and are thicker than normal bones (Cunha, 1990).

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Fluorine

Fig. 14.5 Notice unthrifty appearance of 5-year-old thoroughbred mare with fluoride toxicosis. Enlargement of mandible is from an abscess. (Courtesy of J.L. Shupe, Utah State Agricultural Experimental Station, Logan)

3. SWINE

Fluorosis in swine results in erosion and wearing down of the teeth, softening and overgrowth of the bones, loss of appetite, poor gains, harmful changes in the kidneys, and finally death (Cunha, 1977). In severe cases, the pulp cavities of the teeth may become exposed, causing animals to be reluctant to drink cool water because it pains them to do so. Kick et al. (1935) studied the long-term effects of F on breeding sows and observed no effect on reproduction when up to 650 ppm F (as rock phosphate) was added to the diet. However, feed consumption and, subsequently, lactation were influenced adversely when the diet contained more than 290 ppm F. Although there are few studies in which different levels of F were fed in the same experiment, the available data indicate that both finishing pigs and breeding sows can tolerate at least 150 ppm of dietary F. 4. POULTRY

Fluorine tolerance for poultry is considerably higher than for most other species studied. Maximal safe dietary levels of 300 to 400 ppm F as rock phosphate have been reported for growing chicks and 500 to 700 ppm F from this source for laying hens (Gerry et al., 1949). Tolerance levels similar to those given for chicks have been

Toxicity

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reported for growing female turkeys, but 200 ppm F as the more soluble NaF decreased weight gains in young male turkeys (Anderson et al., 1955). Broilers were able to tolerate F levels of 200 to 400 ppm, however, subacute fluorosis occurred at 800 ppm (Liang and Feng, 1998). Snook (1958) found that neither egg production nor hatchability in chickens was impaired by a diet containing 530 ppm F as rock phosphate. However, egg production and intake were depressed in layers receiving 967 ppm F from rock phosphate (Rao and Reddy, 2001). Fluorine is readily transferred to the eggs of hens consuming high-F diets so that hatchability may be reduced in chronic fluorosis in laying hens (Underwood and Suttle, 1999). The F content in yolk of eggs from hens on a normallow-F diet was raised from 0.8 to 0.9 ppm to as high as 3 ppm by supplementing the hen's diet with 2% raw rock phosphate (Phillips et al., 1935). Hens receiving 20 ppm F (NaF) in drinking water decreased egg production, but eggshell breaking strength was not influenced (Coetzee et aI., 1997). For chickens, 300 to 600 ppm F has been fed with no depression in growth rate. For turkeys, feed consumption was normal at 400 ppm F, slightly decreased at 800 ppm F, and severely curtailed at 1600 ppm F. The growth rate was slightly depressed at 800 ppm F, with a significant depression at 1600 ppm F (NRC, 1974). 5.

OTHER ANIMAL SPECIES

a. Dogs. Dietary F (NaF) at the concentration of 200 to 250 ppm will decrease growth rate of dogs (NRC, 1974). Young pups can tolerate 100 ppm F with no adverse effect on growth. Data are inadequate to determine whether the dental effects caused by this level of ingestion have an adverse effect on mature dogs.

b. Fish. Studies by Neuhold and Sigler (1960) indicated that at levels of 100, 200, and 300 ppm F, there is a linear decrease in hatching time. Because research is limited and because so many factors influence F toxicosis to fish, no F tolerance levels are available (NRC, 1974).

c. Mink. Of all animals studied to date, the mink is the most tolerant, with no toxicosis signs for diets containing 600 ppm F (NaF) (Aulerlich et al., 1987). When diets were increased to 1000 ppm F, adult females and offspring died, as well as having dental and skeletal lesions. d. Laboratory animals. Chronic ingestion of NaF to mice was detrimental to spermatogenesis and androgenesis (Rahmat et al., 1996). Voles receiving high-F diets had reduced weight gains, dental lesions, and between 40 and 100% mortality rate (Boulton et al., 1994, 1997).

e. Bats. Nodular bone lesions were identified in three species of captive fruit bats which received diets high in F (Duncan et al., 1996). Bone from necropsy specimens had high F levels (3300 ppm dry basis).

f Honey bees. Pesticides, rather than industrial emission, are primarily responsible for F intoxication of honey bees. Fluorine-contaminated pesticides

466

Fluorine

characteristically produce acute poisoning and high bee mortality within a few days. Destruction of bees by industrial emissions may occur slowly over the entire season during which the bees are feeding from flowers on which F deposits have accumulated (NRC, 1974). In research cited by Lillie (1970), a F content of more than I ug F per bee was indicative of F pollution. In another study, normal and poisoned bees contained 7.49 and 23 to 47 j!g dry basis per bee, respectively. 6.

HUMANS

Chronic intoxication from F in humans may be derived from water, food, and air; the principal source is water. Generally, surface waters are low in F and contain less than I ppm. However, in a number of localities around the world, the concentration may be as high as 10 to 20 ppm or more. The following industries pose a risk of fluorosis among their workers: (1) aluminum smelters, (2) phosphate fertilizer factories, (3) ceramics, (4) steel industry, and (5) glass industry. Although chronic fluorosis is the main health problem for humans, acute intoxication due to F does occur. After ingesting a large dose of a soluble fluoride, the course of poisoning is violent and brief; deaths are frequently recorded in 2 to 4 hours when an average size adult consumes about 5 g of NaF (RDA, 1989). Nausea, vomiting, and cramping are early symptoms, followed by coma and death. In the United States, deaths from F poisoning (suicidal plus accidental) constitute approximately I% of deaths by poisoning (NRC, 1974). As with animal species, chronic exposure to F affects the skeleton. In children, an excessive F intake causes mottled enamel, with chalky-white patches on the surface of the teeth. Frequently the entire tooth surface is dull white in color, and the enamel becomes pitted and may chip off. Secondarily, the teeth may become stained, and colored from yellow to black. Mottled teeth are structurally weak owing to an interference with the normal development of the enamel. As the stages of skeletal fluorosis progress, symptoms range from occasional stiffness or pain in the joints to chronic joint pain, osteoporosis of long bones, and, in severe cases, muscle wasting and neurological defects. Large populations consume F-contaminated water, especially in developing countries (Gupta et al., 1996). In India, millions of people are crippled by fluorosis (Sangha and Bal, 1998). In a study of 4- to 15-year-old children in an endemic fluorosis area in India, 67.5% had signs of skeletal fluorosis, and of those, 16.5% had crippling deformities (Teotia et al., 1979). Crippling skeletal fluorosis is an advanced stage of chronic F intoxication and often results from the ingestion of 10 to 25 mg F/day for 10 to 20 years (Ophaug, 1990). Skeletal fluorosis is characterized by a progressive hypermineralization of the skeleton, particularly the spinal column and pelvis, calcification of the tendons and ligaments, and exostosis formation. Clinical examination of 542 inhabitants of Tilaipani village, India, revealed a high prevalence of F toxicosis, particularly among inhabitants <20 years of age (51 %) and among males (Chakma et al., 1997). The F content of the main water source from deep-bore wells was in the range 9.22 to 10.82 ppm and the depth 37 to 43 m. A rapid increase in cases of limb deformities had been noted in the

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5 years following the construction of deep-bore wells, with the first case observed 2 years after construction. Sangha and Bal (1998) also noted that fluorosis in India was higher in men as compared to women.

B. Assessment of Fluorine Status No single criterion should be relied on for diagnosing and evaluating F toxicosis (Shupe, 1972). The following clinical signs, lesions, and analytical determinations are of particular diagnostic importance: degree of dental fluorosis; degree of osteofluorosis; intermittent lameness; and the amount of F in the bone, urine, and components of the diet. A sensitive index of F effect is the mottling, staining, and excessive wearing of developing permanent teeth formed during the time of excessive ingestion. Analysis of bone F content and the animal's age give a good indication of potential damage. In dairy cattle, F toxicosis is associated with values, on a dry basis, in excess of 5500 ppm in compact bone and 7000 ppm in cancellous bone, with concentrations between 4500 and 5500 ppm indicating a marginal zone (Suttie et al., 1958). The toxic thresholds for F in the bones of sheep have been placed lower, at 2000 to 3000 ppm dry basis in bulk cortical and 4000 to 6000 ppm dry basis in bulk cancellous bone (Jackson and Wiedmann, 1958). Plasma F values are related to the current rate of F ingestion, with >0.2 mg/l regarded as a critical concentration in cattle (Suttie et al., 1972). For both animals and humans, urinary F is likewise positively related to dietary intake (Singh and Swarup, 1995). With elevated intake, the urinary F levels of cattle increase quickly to 15 to 30 ppm and may reach upper limits of 70 to 80 ppm. Normal cattle have been shown to excrete <5 ppm; those with borderline toxicosis excrete 20 to 30 ppm; and those showing systemic signs of toxicosis excrete > 35 ppm. Other indicators of F status include elevated enzyme levels, hair and nail F levels (Czarnowski et al., 1996), and egg shell F concentration (Machalinski, 1996) for poultry. Serum transaminosis (SGOT and SGPT) were increased in humans (Chinoy et al., 1994) and rats (Grucka et al., 1997) as a result of F toxicosis, indicating alterations in liver functions.

VIII. PREVENTION AND CONTROL OF TOXICITY

To prevent fluorosis, F content of water and supplemental phosphates should be determined along with visual observations to detect early signs of fluorosis. One method of F toxicosis control, although often not practical, is to remove animals from affected areas. Sources of water destined for agriculture or human consumption should be checked for their F contents, whether they are to be consumed directly by humans or animals or used to irrigate forage crops. Sprinkler irrigation with high F-content water will increase the F contents of forage corps more than will flood irrigation. Most plants translocate minimal amounts of F from the soil into their tissues. Livestock should not be allowed to drink water high in F,

468

Fluorine

and if practical, such water should be used to irngate grains vs forage crops. Fluoride contents of wells on ranches where water has induced toxicosis have ranged from approximately 4 to 12 ppm F. Several studies indicate that surface waters contain little F even in endemic fluorosis areas. This has practical relevance, since many endemic fluorosis regions in the world are located in the vicinity of flowing streams. Protected potable water from such sources may be beneficial in the prevention of dental and skeletal fluorosis in both humans and animals. Surface waters from fluorosis areas commonly contain less than I ppm F, whereas the bore waters may contain 5 to 15 ppm F and as much as 40 ppm when evaporation has occurred in troughs or bore drains before consumption by stock (Harvey, 1952). Drinking more fresh water that has not been exposed to evaporation reduces intake of F. Dietary F sources are additive in animals. Therefore, if several components in a diet contain F, their collective total may exceed normal levels and cause F toxicosis. Bone meal and such animal by-products as fish meal, meat and bone scraps, and poultry by-product meals should be taken into account in determining the total F intake (Jones, 1972). Because bone by-product wastes from poultry processing plants are utilized in poultry feeds, it is possible that the F content of poultry bone tissue, especially in integrated operations, will gradually increase over time as the material is recycled. Pesticides (rodenticides, such as fluoroacetate and fluoroacetamide) that come in contact with livestock should be used with care to avoid accidental intakes of the toxicant. It is apparent that P sources manufactured by the furnace process are relatively free of F. Those manufactured from defluorinated phosphoric acid contain safe levels when added to feed supplements and salt mixtures for livestock and meet the recommendation of having not more than one part of F per 100 parts of P. Soft rock phosphate and ground raw rock phosphate generally exceed this ratio by about tenfold and for this reason, should be closely monitored as to both the quantity of F provided and the length of time provided to livestock (Table 14.1). Fluoride in mineral mixtures that are used directly for the feeding of livestock should not exceed 0.20% for dairy and breeding cattle or 0.30% for slaughter cattle, 0.30% for sheep, 0.35% for lambs, 0.45% for swine, and 0.60% for poultry. Properly used, such phosphates are safe for livestock supplementation (Shupe and Olson, 1983). Many nutritionists from developed, industrialized countries make the statement that "only defluorinated phosphates should be fed to ruminants." This is a generally acceptable recommendation since defluorinated phosphates are available and relatively low in cost for developed vs developing countries. Under some circumstances, however, exceeding the upper recommendation of 30 to 50 ppm of F for grazing livestock may be justified. When defluorinated phosphates are unavailable or prohibitively expensive, as occurs in most developing tropical countries, fertilizer or untreated phosphates are recommended, but only for short periods. Successful mineral supplements have been formulated using a mixture of fertilizer phosphates (40%) with defluorinated phosphates (McDowell, 1985). Phosphates containing higher levels of F are more appropriately provided to feedlot

References

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cattle, poultry, and swine than to cattle retained in the breeding herd. It has been suggested that affected areas may be utilized best for the production of animals having a relatively short economic life (e.g., pigs, poultry, or finishing cattle and sheep) and/or for animals having a higher tolerance level for F (e.g., swine and poultry). Calcium given orally or intravenously is known to counteract the effects of F, particularly toxicosis of an acute nature (Krishnamachari, 1987). Feeding of calcium carbonate, aluminum oxide, or aluminum sulfate reduces absorption of F by about a third and thus could offer some control of chronic fluorosis under some conditions. However, free-choice access to a combination of aluminum sulfate with calcium carbonate in a mineral mixture was not effective in reducing bone F deposition in cattle grazing a F-contaminated pasture (Allcroft and Burns, 1969). For poults and chicks, dietary Al at 800 ppm completely prevented toxicosis of 1000 ppm F, but only when given as a sulfate; the oxide form was not effective. Aluminum reduced the gastrointestinal absorption of F (Cakir et al., 1978). Low dietary Ca is also suggested as a strong contributing factor to the severity of fluorosis in humans (Chakma et al., 1997; Teotia et al., 1998). In India, a high intake of Ca in water and food lead to a reduction in the prevalence of fluorosis (Pius et al., 1999). From China, dental fluorosis was lower for milk-consuming children (Chen et al., 1997). From India, diets of people suffering from fluorosis were found grossly deficient in Ca, energy, protein, and vitamin C (Sangha and Bal, 1998). Protein-supplemented diets may substantially mitigate F toxicosis (Chinoy and Mehta, 1999a,b). Magnesium metasilicate has been tested in chronic fluorosis patients, who responded with a partial clinical amelioration of their symptoms (Rao et al., 1975). Studies in rabbits suggest that B given daily in a dose of one-third of the F exposure dose can reduce clinical manifestations of F toxicosis (Elsair et al., 1980). Boron is believed to reduce F absorption by increasing its fecal excretion (Vashishtha et al., 1997).

IX. REFERENCES AAFCO (Assn. of Am. Feed Control Officials). (1973). In "Official Publication," p. 62. Charleston, WV. Allcroft, R., and Burns, K. N. (1969). Fluoride 2,55. Ammerman, C. B., and Henry, P. (1983). Feedstuffs, 55(12), 18. Anderson, J. 0., Hurst, J. S., Strong, D. C, Neilsen, H., Greenwood, D. A., Robinson, W., Shupe, J. L., Binns, W., Bagley, R. A., and Draper, C I. (1955). Poultry Sci. 34,1147. Anke, M., Gurtler, H., Glei, M., Anke, S., Jaritz, M., Freytag, H., and Shafter, V. (1997). In "Proceedings of the Ninth Symposium on Trace Elements in Man and Animals" (P. W. F. Fischer, M. R. L'Abbe, K. A. Cockell, and R. S. Gilson, eds.), p. 192. NRC Research Press, Ottawa, Canada. Araya, 0., Wittwer, F., and Villa, A. (1993). Vet. Human Tax. 35,437. Arnold, eM., Bailey, D. A., Faulkner, R. A., McKay, H. A., and McCulloch, R. G. (1997). Can. J. Public Health 88(6), 388. Aulerlich, R. J., Napolitano, A. C, Bursian, S. J., Olson, B. A., and Hochstein, J. R. (1987). J. Anim. Sci. 65, 1759. Bernstein, D. S., Sadowsky, N., Hegsted, D. M., Guri, C. D., and Stare, F. J. (1966). J.A.M.A. 198,499. Borke, J. L., and Whitford, G. M. (1999). J. Nutr. 129, 1209.

470

Fluorine

Boulton, I. C., Cooke, J. A., and Johnson, M. S. (1994). J. Zoo. London 234(3), 409. Boulton, I. c., Cooke, J. A., and Johnson, M. S. (1997). J. Morph. 232(2), 155. Burt, B. A. (1992). 1. Dent. Res. 71, 1228. Cakir, A., Sullivan, T. W., and Mather, F. B. (1978). Poult. Sci. 57,498. Cao, J., Bai, X., Zhao, Y., Liu, J., Zhou, D., Fang, S., Jia, M., and Wu, J. (1996). Environ. Health Persp. 104(12), 1340. Cao, J., Zhao, Y., Liu, J., Bai, X., and Wang, E. (1997). Acta. NutI'. Sinica 19(3), 310. Carlson, C. H., Armstrong, W. D., Singer, L., and Hinshaw, L. B. (1960). Am. J. Physiol. 198,829. Cerklewski, F. L. (1997). In "Handbook of Nutritionally Essential Mineral Elements" (B. L. O'Dell and R. A. Sunde, eds.), p. 583. Mercel Dekker, Inc., NY. Cerklewski, F. L., and Ridlington, J. W. (1987). In "Trace Element Metabolism in Man and Animals (TEMA-6)." (L. S. Hurley, C. L. Keen, B. Lonnerdal, and R. B. Rucker, eds.), p. 45. Plenum Press, NY. Chakma, T., Singh, S. 8., Godbole, S., and Tiwary, R. S. (1997). Ind. Ped. 34(3),232. Chavassieux, P., and Meunier, P. J. (1995). Arch. Pedia. 2(6), 568. Chen, Y. X., Lin, M. Q., Xiao, Y. D., Gan, W. M., Min, D., and Chen, C. (1997). Fluoride 30(2), 77. Chinoy, N. J., Barot, V. V., Michael, M., Barot, J. M., Purohit, R. M., Ghodasara, N. G., and Parikh, D. J. (1994). J. Envir. Bioi. 15(3), 163. Chinoy, N. J., and Mehta, D. (I 999a). Fluoride 32(4),204. Chinoy, N. J., and Mehta, D. (1999b). Fluoride 32(3), 162. Clay, A. B., and Suttie, J. W. (1981). Am. Soc. Anim. Sci., Proc. Ann. Meet. 72nd, p. 352 (Abstr.). Coetzee, C. B., Casey, N. H., and Meyer, J. A. (1997). Brit. Poult. Sci. 38(5), 597. Cunha, T. J. (1977). "Swine Feeding and Nutrition." Academic Press, NY. Cunha, T. J. (1990). "Horse Feeding and Nutrition." Academic Press, NY. Czarnowski, W., Stolarska, K., Brzezinska, B., and Krechriak, J. (1996). Fluoride 29(3), 163. Dean, H. T. (1942). In "Fluorine and Dental Health" (R. Moutton, ed.), p. 6. American Association of Advanced Science, Washington, D.C. DePaola, D. P., Faine, M. P., and Vogel, R. I. (1994). In "Modern Nutrition in Health and Disease" (M. E. Shils, J. A. Olson, and M. Shike, eds.), Vol. 2, 8th Ed., p. 1007. Lea and Febiger, Philadelphia, PA. Desai, V. K., Solanki, D. M., Kantharia, S. L., and Bhavsar, B. S. (1993). Fluoride 26(3), 181. Doberanz, A. R., Kurnick, A. A., Kurtz, E. G., Kemmerer, A. R., and Reid, B. L. (1963). Fed. Proc. 22, 533 (Abstr.). Dominok, G., Siefert. K., Freige, J., and Dominok, B. (1984). Fluoride 17, 23. Duncan, M., Crawshaw, G. J., Mehren, K. G., Pritzker, K. P. H., Mendes, M., and Smith, D. A. (1996). J. Zoo. Wildlife Med. 27(3), 325. Dunipace, A. J., Brizendine, E. J., Wilson, M. E., Zhang, W., Katz, B. P., and Stookey, G. K. (1998). J. NutI'. 128, 1392. Ekstrand, J., Fomon, S. J., Ziegler, E. E., and Nelson, S. E. (1994). Pediatr. Res. 35, 157. Elsair, J., Merad, R., Denine, R., Reggabi, M .. Alamir, B., Benali, S., Azzouz, M .• and Khelafat, K. (1980). Fluoride 13, 129. Ergun, H. S., Riissel-Sinn, H. A., Baysu, N., and Diindar, Y. (1987). Dtsch, Tierarztl. Wschr. 94, 381. Farrerons, J., Rodriguez de la Serna, A., Guanabens, N., Armadans, L., Lopez-Navidad, A., Yoldi, B., Renau, A., and Vaque, J. (1997). Calcif. Tiss. Inter. 60(3),250. Geeson, N. A., Abrahams, P. W., Murphy, M. P., and Thornton, I. (1998). Agric. Ecosystems En vir. 68(3),217. Gerry, R. W., Carrick, C. W., Roberts, R. E., and Hauge, S. M. (1949). Poult. Sci. 28, 19. Godoy, S.• and Chicco, C. F. (1997). Arch. Latinoamericanos de Produccion Animal 5(1), 235. Grernbowski, D., Fiset, L., and Spadafora, A. (1992). J. Am. Dent. Assoc. 123,49. Grucka, M. E" Machoy, M., Tarnawski, R., Birkner, E., and Mamczar, A. (1997). Fluoride 30(3), 157. Gupta, S. K., Gupta. R. C., Seth, A. K., and Gupta, A. (1996). Acta Ped. Japonica 38(5),513. Gutierrez, 0., Marrero, A. I., Terry, I., Cairo, J. (1993). Cuban J. Agri. Sci. 27(3), 319. Harvey, J. M. (1952). Queensland J. Agric. Sci. 9, 47. Hobbs, C. S., and Merriman, G. M. (1962). "Fluorosis in Beef Cattle." Tenn Agric. Exp. Stn. Bull. 351. Knoxville, TN. Hunt, C. D., and Stoecker, B. J. (1996). J. Nutr. 126, 2441s. Jackson, D., and Wiedmann, S. M. (1958). J. Pathol. Bacteriol. 76,451. Jones, W. G. (1972). Vet. Rec. 90, 503. Jubb, T. F., Armand, T. E., Main, D. c, and Murphy, G. M. (1993). Aust. Vet. J. 70(10), 379. Kapoor, V., Prasad, T., and Paliwal, V. K. (2002). Indian J. Anim. Sci. 72, 80.

References

471

Kick, C. H., Bethke, R. M., Edgington, B. H., Wilder, O. H. M., Record, P. R., Wilder, W., Hill, T. 1., and Chase, S. W. (1935). "Fluorine in Animal Nutrition." Ohio Agric. Exp. Stn. Bull. 588. Kierdorf, U., and Kierdorf, H. (2000). J. Zoo. 250(1), 87. Kierdorf, U., Kierdorf, H., Sedlacek, F., and Fejerskov, D. (1996). J. Anatomy 188(1), 183. Kirk, K. L. (1991). "Biochemistry of the Halogens and Inorganic Halides." p. 19. Plenum Press, NY. Kleerekoper, M., and Balena, R. (1991). Ann. Rev. Nutr. 11,309. Krishnamachari, K. A. V. R. (1987). In "Trace Elements in Human and Animal Nutrition." (W. Mertz, ed.), p. 365. Academic Press, NY. Liang, X. Q., and Feng, D. Y. (1998). Acta Vet. Zootec. Sinica 29(6),517. Lillie, R.I. (1970). "Air Pollutants Affecting the Performance of Domestic Animals - A Literature Review." Agriculture Handbook No. 380. U.S. Department of Agriculture. Government Printing Office, Washington, D.C. Machalinski, B. (1996). Roczniki Pomorskiej Akademii Medycznej w Szczecinie 42, 25. Maltz, M., and Emilson, C. G. (1982). J. Dent. Res. 61, 786. Mandel, I. D. (1979). Am. Scientist 67, 680. Marais, 1. (1943). Onderstepoort J. Vet. Sci. Anim. Ind. 18,203. McDowell, L. R. (1985). "Nutrition of Grazing Ruminants in Warm Climates." Academic Press, NY. Merriman, G. M., and Hobbs, C. S. (1962). "Bovine Fluorosis from Soil and Water Sources." Tenn. Univ. Agric. Exp. Stn. Bull. No. 347. Knoxville, TN. Messer, H. H., Armstrong, W. D., and Singer, L. (1973). J. Nutr. 103, 1319. Mittal, 1. P., Djajanegara, A., and Sukmawati, A. (1994). In "Proceedings of the 7th AAAP Animal Science Congress." 2,485. Bali, Indonesia. Murray, T. M., Ste-Marie, L. G. (1996). Can. Med. Assoc. J. 155(7),949. Mwaniki, D. L., and Gikunju, 1. K. (1995). Discovery and Innovation 7(2),173. NCHS (National Center for Health Statistics). (1992). Prevention Profile. Health, United States 1991. Public Health Service, Hyattsville, MD. Neuhold, 1. M., and Sigler, W. F. (1960). Trans. Am. Fish Soc. 89, 363. Nielsen, F. H. (1996). J. Nutr. 126, 2377s. Nopakun.l., Messer, H. H., and Voller, V. (1989). J. Nutr. 119, 1411. NRC. (1971). "Fluorides." National Research Council- National Academy of Sciences, Washington, D.C. NRC. (1974). "Effects of Fluorides in Animals." National Research Council - National Academy of Sciences, Washington, D.C. NRC. (1980). "Mineral Tolerance of Domestic Animals." National Academy of Sciences - National Research Council, Washington, D.C. Ophaug, R. H. (1990). In "Nutrition Reviews: Present Knowledge in Nutrition" (6th Ed.) (M. L. Brown, ed.), p. 274. International Life Sciences Institute Nutrition Foundation, Washington, D.C. Phillips, P. H., Greenwood. D. A., Hobbs, C. S., and Hoffman, C. F. (1955). "The Fluorosis Problem in Livestock Production," Nat. Res. Council Pub. 381, Washington, D.C. Phillips, P. H., Halpin, 1. G., and Hart, E. B. (1935). J. Nutr. 10,93. Phipps, K. R. (1996). In "Present Knowledge in Nutrition" (E. E. Ziegler and L. 1. Filer, eds.), p. 329. ILST Press, Washington, D.C. Pierce, A. W. (1959). Aust . J. Agric. Res. 10, 186. Pius, A., Apparao, B. V., and Karthinkeyan, G. (1999). Ind. J. Envir. Health. 41(2). 121. Raffi, M. B., Mendez, M. c., and Riet-Correa, F. (1997). Pesq. Vet. Bras. 17(2),69. Rahmat, B., Sudhir, S., Lall, S. B., Bano, R., and Sahdev, S. (1996). Indian J. Environ. Toxic. 6(1),19. Rao, S. R., Murthy, K.l. R., Murthy, T. V. S., Reddy, S. S., and Saxena, M. K. (1975). Fluoride 8,144. Rao, S. V. R., and Reddy, V. R. (2001). Brit. Paul. Sci. 42, 376. RDA. (1989). "Recommended Daily Allowances," 10th Ed. Food and Nutrition Board, National Academy of Sciences, Washington, D.C. Reginster, J. Y., Meurmans, L., Zegels, B., Rovati, L. C., Minne, H. W., Giacovelli, G., Taguet, A. N., Setnikar, I., Collette, J., and Gosset, C. (1998). Annals Inter. Med. 129, 1. Roholm, K. (1937). "Fluorine Intoxication: A Clinical-Hygienic Study with a Review of the Literature and Some Experimental Investigations," H. K. Lewis and Co., London, England. Samal, U. N., and Naik, B. N. (1995). Environ. Ecol. 13(2),4[5. Sangha, 1. K., and Bal, S. K. (1998). J. Human Ecol. 9(2), [59. Santos, R. L., Nunes, V. A., and Ferreira, W. M. (1996). Arg. Brasileiro Med. Vet. Zoo. 48(3), 295. Schultheiss, W. A., and VanNiekerk, J. c., (1994). J. So. Afr. Vet. Assoc. 65(2), 84. Schwarz, K., and Milne, D. B. (1972). Nature (London) 239, 333. Shupe, J. L. (1972). In "Equine Medicine and Surgery," p. 215. American Veterinary Publications, Wheaton. [L.

472

Fluorine

Shupe, J. L., Miner, M. L., Harris, L. E., and Greenwood, D. A. (1962). Am. J. Vel. Res. 23, 777. Shupe, J. L., and Olson, A. E. (1971). J. Am. Vel. Med. Assoc. 158, 167. Shupe, J. L., and Olson, A. E. (1983). In "Fluorides" (J. L. Shupe, J. P. Peterson, and N. C. Leone, eds.), p. 319. Paragon Press, Salt Lake City, UT. Singer, L., and Ophaug, R. H. (1984). "Nutrition Reviews: Present Knowledge in Nutrition," 5th Ed. (R. E. Olson, H. P. Broquist, C. O. Chichester, W. J. Darby, A. C. Kolbye, and R. M. Stalvey, eds.), p. 538. The Nutriton Foundation, Inc., Washington, D.C. Singh, J. L., and Swarup, D. (1995). Agri-Practise 16(5), 25. Singh, J. L., Swarup, D., Dogra, R. K. S., and Singh, G. R. (1995). Ind. J. Anim. Sci. 65(2), 162. Snook, L. C. (1958). J. Dept. Agric. W. Ausl. 7, 545. SUllie, J. W. (1969). J. Agric. Food Chem. 17, 1350. SUllie, J. W., Carlson, J. R., and Faltin, E. C. (1972). J. Dairy Sci. 55, 790. SUllie, J. W., and Fallin, E. C. (1973). Am. J. Vel. Res. 34,379. SUllie, J. W., Miller, R. F., and Phillips, P. H. (1957). J. Dairy Sci. 40, 1485. SUllie, J. W., and Phillips, P. H. (1960). J. Nutr. 71, 109. SUllie, J. W., Phillips, P. H., and Miller, R. F. (1958). J. Nutr. 65, 293. Swamp, D., Dwivedi, S. K., Day, S., and Ray, S. K. (1998). Ind. J. Anim. Sci. 68(7), 605. Tao, S., and SUllie, J. W. (1976). J. Nutr. 106, 1115. Teotia, M., Teotia, S. P. S., and Singh, R. K. (1979). Ind. J. Ped. 46, 389. Teotia, M., Teotia, S. P., and Singh, K. P. (1998). Ind. J. Ped. 65(3), 371. Teotia, S. P. S., and Teotia, M. (1994). Fluoride 27(2),59. Thompson, D. J. (1978). In "Proceedings Latin American Symposium on Mineral Nutrition Research with Grazing Ruminants" (J. H. Conrad, and L. R. McDowell, eds.), p. 47 and 73. Univ. of Florida, Gainesville, FL. Underwood, E. J. (1977). "Trace Elements in Human and Animal Nutrition" Academic Press, NY. Underwood, E. J., and Suttle, N. F. (1999). In "The Mineral Nutrition of Livestock" (3rd Ed.), Midlothian, UK. Van Wazer, J. R. (1961). In "Phosphorus and Its Compounds" Vol. 2, p. 1025. Interscience, NY. Vashishtha, S. N., Kapoor, V., Yadav, P. S., and Mandai, A. B. (1997). Fluoride 30(3), 165. Weber, C. W. (1966). "Fluoride in the Nutrition and Metabolism in Experimental Animals." Ph.D. Thesis, University of Arizona, Tucson, AZ. WHO (World Health Organization) (1996). In "Trace Elements in Human Nutrition and Health" p. 187. World Health Organization, Geneva. Zipkin, I. E., Zucas, S. M., and Stillings, B. R. (1969). J. Nutr. 100,293.