1979 Fluoride Abstracts. Fluoride Action Network Pesticide Project.

Book Review

Proiswodstwennyj Fljuoros [Industrial Fluorosis]

[Russian]

NA Bogdanow and EW Gembizkij

Medizina, Leningrad 1975, 95 pp., 24 tables, 10 figures

Excerpt from Review:
... Chapter 2 deals with the usual features of chronic fluoride intoxication. It refers to the literature, particuarly with reference to chronic changes in addition to those of the skeletal system. The authors quote primarily authors of the U.S.S.R., with a predominance of early publications... Chronic inflamatory changes of the skin, the eyes and the upper respiratory tract (chronic rhinitis, laryngitis and pharynigitis) are reported; moreover functional disturbances of the central nervous systems ("astheno-vegetative syndrome and diffuse damage of the CNS"), circulatory disturbances (bradycardia, hypotension and changes in the EKG), gastric and intestinal disorders, damage to liver and kidneys and dysfunction of endocrine organs, particularly of the thyroid, the parathyroid and the adrenal cortex. In the conclusion of this chapter alterations of the mineral metabolism are discussed...

Fluoride 1979; 12(2):65-71

Effect of sodium fluoride on adrenal gland of rabbit. I. Studies on ascorbic acid and Delta 5-3Beta hydroxysteriod dehydrogenase activity

K Rao * and AK Susheela **

* National Institute of Nutrition, Hyderabad, India
** Fluorosis Research Laboratory, Dept. of Anatomy, All India Institute of Medical Sciences, New Delhi.

Summary: Rabbits were given 50 mg sodium fluoride/kg body weight through the intragastric route every 24 hours for a total period of 200 days. The left adrenal gland was removed and its total weight recorded. Adrenal glans from rabbits sacrificed at varying intervals for other investigative purposes were also collected and their weights recorded. The data indicate a significant rise in the total weight of the gland.

Both ascorbic acid and steroid dehydrogenase (Delta 5-3-Beta hydroxysteroid dehydrogenase) were localized in the adrenal gland by histochemical methods. The results indicate that, in rabbits exposed to NaF, a reduction in ascorbic acid content as well as a depletion of steroid deydrogenase activity occurs especially at the zona glomerulosa.

The significance of the increase in the weight of the gland to the reduction of the ascorbic acid content and steroid dehydrogenase activity is discussed.

Note from EC: Zona glomerulosa is the outer layer of the cortex of the suprarenal gland just beneath the capsule; secretes aldosterone. Ref: Stedman's Concise Medical Dictionary for the Health Professions. Illustrated 4th Edition. Ed. JH Dirckx MD. 2001. Lippincott Williams & Wilkins.

Fluoride 1979; 12(3):114-124

The synthesis of fluorocitrate from fluoroacetate in isolated rat mitochondria

Buffa P, Costa-Tiozzo R, Gualtieri-Fruggeri M

Instituto di Patologia Generale, Universita di Modena, Italy

Excerpt from Summary: The synthesis of florocitrate was studied in isolated rat liver, brain, kidney and heart mitochondria. Evidence was obtained of fluorocitrate formation in liver, brain and kidney mitochrondria but not in heart mitochondria.

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=469843&dopt=Abstract

J Reprod Fertil 1979 May;56(1):201-7

Effects of fluoroacetate on the testis of the rat.

Sullivan JL, Smith FA, Garman RH.

Rats recieving 20, 6.6 or 2.2 p.p.m. sodium fluoroacetate in the drinking water were killed daily during the 7 days of treatment and at more widely spaced intervals in the succeeding 21 days. Testicular weight and ATP concentrations decreased in rats receiving 20 or 6 p.p.m. fluoroacetate, while citrate concentrations were elevated and morphological damage was seen in the testes of all the treated rats. Initial cellular changes common to the three treatment groups included altered appearance and decreased numbers of spermatids, and formation of spermatid and spermatocyte giant cells. At the two higher concentrations damage progressed to marked seminiferous tubule atrophy. Regeneration of the seminiferous tubules was complete by 7 days after treatment, in the rats given 2 p.p.m. but regeneration was not complete by Day 21 after treatment in those receiving the higher doses. Spermatogenesis was abnormal in some instances during the regneration period in these groups. The findings are consistent with impaired energy production via blockage of the Krebs cycle, and subsequent impairment of carbohydrate metabolism through the Embden-Meyerhof pathway.

PMID: 469843 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=423164&dopt=Abstract

J Reprod Fertil 1979 Jan;55(1):69-74

Effects of phenylmethylsulphonylfluoride on activities of cholesteryl ester synthesis and hydrolysis in testes of rats, and on serum testosterone and LH levels.

Takatori T, Yamaoka A.

PMSF was injected subcutaneously to male rats once a day for 10 days at a dose of 10 mg/day. There was an increase in the concentrations of free and esterified cholesterol in the testes, a decrease in activities of cholesteryl ester synthesis and hydrolysis but no change in activity of cholesterol side-chain cleavage enzyme. Serum testosterone and LH levels were significantly decreased. The only effect of PMSF on the lipids of the testes was a marked elevation of docosapentaenoic (22:5) acid and the cholesteryl esters.

PMID: 423164 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=40394&dopt=Abstract

Acta Pharmacol Toxicol (Copenh) 1979 Aug;45(2):96-101

Fluoride inhibition of protein and DNA synthesis in cells in vitro.

Holland RI.

Fluoride concentrations at and above 0.9 mM caused a progressive, concentration-related inhibition in the incorporation of both 14C-leucine and 3H-thymidine in LS cells incubated in medium with serum. The incorporation of leucine was more affected than that of thymidine. Lowering the pH enhanced the effect of fluoride on both. Removing serum from the incubation medium changed the effect of fluoride, particularly at low pH (7.0). Incorporation of leucine was then stimulated by low fluoride concentrations (0.5 and 0.9 mM), and the effect on thymidine incorporation was eradicated up to 1.3 mM-NaF. No differences were found in the pool and the specific activity of 14C-leucine in the fluoride exposed cells compared to control cells without fluoride (incubated at pH 7.4 in medium without serum). The cellular pool of 3H-thymidine decreased markedly during the incubation period, somewhat less in the fluoride exposed cells than in the control.

PMID: 40394 [PubMed - indexed for MEDLINE]

Acta Pharmacol and Toxicol 1979; 45:302-305

As cited and abstracted in Fluoride 1981; 14(1):43

Fluoride inhibition of DNA synthesis in isolated nuclei from cultured cells

RI Holland

Fluoride inhibits protein and DNA synthesis in LS cells. The author elucidted the mechanism for this effect by isolating DNA synthesizing nuclei from LS cells and from LS cells resistant to 6mM (114 ppm) fluoirde. Fluoride concentrations of 1.5 mM (28.5 ppm) had no effect, but 3 and 6mM inhibited DNA synthesis in both groups of cells, the sensitive and the resistant cells. In intact cells - as distinguished from their nuclei - fluoride affects exclusively the DNA synthesis in sensitive cells. Their intracellular fluoride concentration is only 30 to 40% of that of the extracellular concentration. Inhibition of DNA synthesis by fluoride is secondary to fluoride inhibition of protein synthesis.

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=474145&dopt=Abstract

Acta Pharmacol Toxicol (Copenh) 1979 May;44(5):350-3

Effect of sodium fluoride on protein and DNA synthesis, ornithine decarboxylase activity, and polyamine content in LS cells.

Hongslo JK, Holland RI.

Sodium fluoride exhibited a dose dependent inhibitory effect on protein and DNA synthesis at concentrations from 1.3 mM in growing LS cells. The activity of ornithine decarboxylase (ODC) was slightly stimulated by 0.5 mM-NAF, but inhibited at 1.3 mM and above. The reduced enzyme activity seemed to be due to a reduced de novo formation of the enzyme caused by an inhibition of the protein synthesis. In spite of a reduction of ODC-activity, fluoride had no effect on the cellular polyamine content during the experimental period (10 hours).

PMID: 474145 [PubMed - indexed for MEDLINE]

Cell Biol Int Rep 1979; 3:701-705

As cited ("Fluoride Briefs") in Fluoride 1980; 13(4):173

Fluoride inhibition of protetin synthesis

RI Holland

Fluoride inhibits protein synthesis in all types of mammalian cells investigated so far by inhibiting the initiation of new peptide chains and by acting on the disassociation of 80S ribosome to 40S and 60S ribsomal subunits. It does not affect the peptide chain elongatinprocess after initiation.

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=554915&dopt=Abstract

Med Lav 1979 Sep-Oct;70(5):363-8

No Abstract available

First experimental evidence of the carcinogenic effects of vinylidene fluoride; long-term bioassays on Sprague-Dawley rats by oral administration.

Maltoni C, Tovoli D.

PMID: 554915 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=435251&dopt=Abstract

Biochem J 1979 Feb 1;177(2):549-58

Rapid aging of neurotoxic esterase after inhibition by di-isopropyl phosphorofluoridate.

Clothier B, Johnson MK.

PMID: 435251 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=420295&dopt=Abstract

Am J Physiol 1979 Feb;236(2):F141-8

Fluoride tissue distribution: short-term kinetics.

Whitford GM, Pashley DH, Reynolds KE.

The short-term distribution kinetics of 18F, with and without added carrier, were studied in 12 soft tissues and femur following intravenous administration in rats. The animals were killed in groups of four at 5, 10, 15, 20, 30, and 60 min after the dose. A tissue was judged to be kinetically homogeneous with plasma if an early and constant tissue water-to-plasma (T/P) 18F concentration ratio was established. In the carrier-free study, liver, heart, skin, fat, and kidney met this criterion. In the presence of carrier, four other tissues were added to this group. Brain, resting skeletal muscle, spleen, and femur did not achieve constant T/P values. The addition of carrier resulted in significantly lower T/P ratios in nine tissues. This was especially marked in femur. It is concluded that
1) none of the soft tissues studied strongly binds 18F;
2) most of these tissues are kinetically homogeneous with plasma; and
3) the presence of carrier fluoride can significantly influence the kinetic behavior and distribution of 18F.
Finally, based on the current and previously reported 18F T/P ratios, and on reported intracellular-extracellular pH gradients, it is hypothesized that fluoride distribution in several soft tissues is determined by the diffusion equilibrium of HF, that is, by the magnitude of the transmembrane pH gradient.

PMID: 420295 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=231654&dopt=Abstract

J Med Chem 1979 Dec;22(12):1493-7

Synthesis and biological properties of 2-, 5-, and 6-fluoronorepinephrines.

Kirk KL, Cantacuzene D, Nimitkitpaisan Y, McCulloh D, Padgett WL, Daly JW, Creveling CR.

2-Fluoro-, 5-fluoro- and 6-fluorodimethoxybenzaldehydes were prepared by photochemical decomposition of the corresponding diazonium fluoroborates. The aldehydes were converted to the cyanohydrin trimethylsilyl ethers, which, in turn, were reduced to the dimethoxyphenethanolamines. Boron tribromide demethylation afforded the racemic ring-fluorinated norepinephrines. An alternate route, using the dibenzyloxyfluoroaldehyde, was also used to prepare 6-fluoronorepinephrine. The fluorine substituent markedly increases the phenolic acidities of these analogues. The biological properties conferred upon norepinephrine by the fluorine substituents in peripheral and central adrenergically responsive systems clearly demonstrate that 2-fluoronorepinephrine is a nearly a pure beta-adrenergic agonist, while 6-fluoronorepinephrine is an alpha-adrenergic agonist. 5-Fluoronorepinephrine retains both beta- and alpha-adrenergic agonist properties. Receptor-binding studies with specific radiolabeled ligands indicate that the specificity conferred by the site of fluorine substituents results from a change in the affinity of these analogues for the alpha- and beta-adrenergic receptors.

PMID: 231654 [PubMed - indexed for MEDLINE]

J Assoc Off Anal Chem 1979; 62:1054-1061

As cited in Fluoride 1980; 13(3):99

Lead, fluoride and other elements in bonemeal supplements

SG Capar and JH Gould

Twenty commercial bonemeal supplements were analyzed for their mineral content. Their lead concentration ranged between 1.5 and 8.7 ug/g, cadmium 0.05-2.5 ug/g. Their fluoride range was between 261 and 921 ug/g.

Human renal fluoride excretion: alterations observed in chronic renal failure (a preliminary report)

Section of Nephrology, Department of Internal Medicine, University of Zurich, Switzerland

Summary: The mechanism of renal fluoride excretion by the human kidney is glomerular filtration and tubular reabsorption. Higher fluoride clearances than those for creatinine were never observed indicating that tubular secretion of floride can be excluded. Patients suffering from renal diseases tend to continue to excrete normal dietary loads of fluoride quite well until renal excretory function is reduced to 1/4 of normal. In chronic renal failure, elevatin of plasma fluoride is delayed and less than might be expected from impairment of flomerular filtratin rate, because tubular reabsorption diminishes. End stage renal disease is characterized by elevated plasma fluoride concentrations and excessive deposition in the bone.

The relationship of fluoirde to visible growth/health characteristics of Pinus monticola, Pinus controta, and Pseudotsuga menziesii

Summary: An intensive field study during the summer of 1977 near an aluminum plant in northwestern Montana, U.S.A., was initiated to determine the relationship of foliar-accumulated fluoride to various growth/health characteristics of three commercially-important conifer species. Regression techniques were used to analyze the data obtained from nearly 110,000 needles. Increasing foliar concentrations of fluoride in Pseudotsuga menziessi were associated with decreased needle retention and length, and with increased tip necrosis. Both mottle and tip necrosis of Pinus contorta increased in direct relation to the concentration of fluoride, whereas needle retention decreased. Tip necrosis and mottle of Pinus monticola also increased with foliar fluoride. No threshold foliar fluoride concentration was observed; adverse effects were visible on needles when their fluoride concentration reached 8-10 ppm, on a dry weight basis. Control concentrations were 3-5 ppm. It is concluded that no emission of atmospheric fluoride will truly protect coniferous vegetation.

Summary: The bone mineral content and the width of the left radius of persons with long-term fluoride exposure were determined by means of the bone mineral analyzer. Observations were made on 245 aluminum smelter workers exposed to high atmospheric floride and compared to 292 workers in another aluminum factory with lower fluoride exposure. A third group consisted of 485 persons, whose drinking water has an average fluoride content of 2.5 ppm. All measured values were compared to normal values. We found an increase of bone mineral content and especially of the bone width which was dependent on the fluoride exposure (level and time). Photo-absorptiometry permits an early recognition of fluoride-dependent changes in bones and is suitable for follow-up studies on persons with long-term exposure to fluoride.

* The following is the only report on this subject known by the authors: JO Ares 1978. Fluoride cycling near a coastal emission source. JAPCA 28:344-349.

The effect of fluoride on the polyphenoloxidase and peroxydase activities of tobacco leaves (Nicotina tabacum L. VAR PN 91)

by George L. Waldbott, M.D., in collaboration with Albert W. Burgstahler, Ph.D. and H. Lewis McKinney, Ph.D.

1979. 423 pages, 45 illustrations, 35 tables. Coronado Press, Inc., Lawrence, Kansas.

Note from FAN: Simply put, anyone with an interest in fluoride should buy this book. Even though it is out of print you can still purchase a copy from Amazon.com for as low as $10.00. - EC.

Residue Reviews [Edit. FA Gunther] 1977; 68:37-57
Springer Verlag, New York, Heidelberg, Berlin

As abstracted in Fluoride 1979; 12(1):54:
The authors, in the Department of Food Chemistry and Technology, University of Helsinki, Finland, review the fluoride content of foods of animal and vegetable origin, as well as the effects of fluoirdated water and of processing and preparation of food on its fluoride content. They also discuss the different fluoride compounds present in certain foods and the average daily fluoirde intake in various countries. In explanation of their findings, they investigated the role of fluoride from rock beds, soil and air as sources of contamination of the environment, especially of food. They recommend that national, local and individual food habits be taken into account when fluoridation of drinking water is contemplated. In food of plant origin, they state that tea and spinach contain the highest amounts of fluoride whereas in food of animal origin marine fish ranks highest.

The authors recommend control of fluoride levels in commercially prepared food, espcially in those items destined to be a principal food source, such as baby foods. They poiint out that teflon-coated cooking vessels may increase the fluoride content of food. Sixteen tables make the review particularly luck and the 56 well-chosen references ensure a balanced approach to the problem.

Metabolism of fluoride in pregnant women residing in endemic fluorosis areas

Department of Human Metabolism and Endocrinology, L.L.R.M. Medical College, Meerut, India

Summary: Free ionic fluoride concentrations were measured in the maternal blood plasma, cord blood plasma and the urine of pregnant and age matched nonpregnant women in two groups of subjects. Group 1included females who had been living in endemic fluorosis areas with the mean intake of 21 mg/day of fluoride from drinking water and Group 2 consisted of women from non-endemic areas with the mean daily intake of 1.5 mg of fluoride from drinking water. The ionized fluoride concentrations in the maternal plasma and the urine decreased during the course of pregnancy: they were at their lowest at 36 weeks of gestation. In the nonpregnant controls these values remained largely unchanged. In the maternal and cord blood plasma obtained at the time of cesarean section the fluoride concentrations were similar and did not support the concept of a placental fluoride barrier. The higher fluoirde content in the plasma and urine of the women in the endemic group (10 ppm F in drinking water) indicated a direct relationship of these values to the amount of fluoride ingested. The fall in the maternal plasma and urine fluoride concentrations during pregnancy is belieed to be due to increasing accumulation of fluoride in the rapidly mineralizing fetal skeleton.

Bagga OP, Mehta SP, Parkash V, Raizada A, Singh KN, Sankhyan KA, Gupta R, Sood B

Mass poisoning in dogs due to meat contaminated by sodium fluoroacetate or fluoroacetamide (special reference to the differential diagnosis)

Summary: The results of laboratory invetigations are reported in a mass poisoning at which time about 800 dogs died shortly after consuming purchased poultry meat. Clinical and pathological findings were suggestive of poisoning by either strychnine, sodium fluoroacetate (FAC) or fluoroacetamide (FAA). Toxicological examinations implicated organofluorides. At the convulsive stage, the clinical symptoms of FAC (or FAA) and strynchnine poisoning are similar and the pathological lesions may be identical. Therefore, toxicological analysis and bio-assays are required for an accurate diagnosis. The toxicological and public health implications of mass poisoning are discussed.

Excerpts: [Strychnine, FAC or FAA are used in bait for rodent control.] ... On the basis of toxicological findings, the meat was found to be contaminated with either FAC or FAA and the cause of death in the dogs was poisoning by one of these compounds... FAA is metabolized to FAC in the body and therefore the original toxicant cannot be determined solely on a chemical basis. We do not know whether the poultry was incorporated into the dog food after emergency slaughter consequent to FAC or FAA poisoning or whether the fowl had subclinical poisoning. The latter is a possibility because of the relatively high LD50 of FAA in chickens... Relatively few reports of FAC or FAA poisoning in dogs have appeared. The most publicized case occurred in England in 1963, when the meat of a pony found dead was subsequently sold for animal consumption. Within the next two days about 100 dogs and cats died after eating the meat. This incident led the British to restrict usage of FAA as a rodenticide soley to ships and sewers...

Changes in glucose-6-phosphatase activities in kidney and liver of rats after administration of a single dose of fluoride

Measuring of cortical thickness, a means for controlled diagnosis of fluoride-exposed people

Summary: In 230 aluminum workers, 5662 measurements were made on the radiographs of the thorax and the extremities. The cortical index of the clavicle, 4th rib,tibia, and fibula were determined by means of a measuring magnifier and a pair of compasses. The determination of the cortical index of the 4th rib is recommended for the early diagnosis of skeletal fluorosis, because this bone appears to be least affected by outside influences and because it showed the most distinct increases of the cortical index.

Functional changes in the salivary glands of rats after sodium fluoride treatment

One to 10 ppm fluroide added to drinking water enchance the activity of carbonic anhydrase in the submandibular salivary gland of rats. With 25 ppm fluoride in drinking water, the fluoride content of the parotid gland increased considerably. It is concluded that fluoride affects the function of the salivary gland.

As abstracted in Fluoride 1979; 12(2):102-103.
Excerpts: The author describes what appears to be an epidemic of neighborhood fluorosis in 23 individuals residing within 1/4 to 3 miles of an Ohio frit producing factory, in operation since 1966. On the side facing the factory vegetation showed characteristic fluoride changes at tips and margins of foliage. The tooth and bone of a dog which had died in convulsions contained 1480 and 2050 ppm fluoride respectively. In pine needles and leaves, fluoride levels ranged up to 53.6 ppm.

Of the 23 individuals, 7 were males and 16 were females aged 9 to 76 with a mean of 40.7 Nine of the 23 patients were examined; four of them hospitalized at Hutzel Hospital, Detroit. Only 1 of the 23 was a smoker and none were habitual tea drinkers. In a family of four, every member and, in another family, four out of five members were adversely affected.

In every case, generalized progressive fatigue was an outstanding feature. Other typical characteristics were a distinct decline in mental acuity, forgetfulness, inability to coordinate thoughts, and even reduced ability to write and to form words.

All individuals complained of pains in muscles and joints. Eleven exhibited muscular fibrillation, 8 retrosternal pain, and 3 bursitis. All, but one, complained of symptoms referrable to the central nervous system, i.e. paresthesias in arms and legs, headaches and vertigo; in 7, visual changes occurred.

... The severity of the disease correlated with the distance of the patients' residence from the factory. Persons absent from their home during the day were less affeced than those confined to their homes. All patients were well balanced individuals who did not exaggerate their complaints.

Physical and laboratory findings were sparse and inconsistent. X-ray examinations failed to exhibit the changes usually associated with skeletal fluorosis. The 24-urinary fluoride excretion in 21 patients ranged from 0.35 to 2.4 mg/day and was directly related to the distance of their residence from the factory.

Long-term effects of fluoride administration in rabbits - an experimental study. iii) Histological changes in the parathyroid and correlation with changes in the bone

Summary: In rabbits given daily subcutaneous injections of sodium fluoride in doses ranging from 0.5 mg/kg to 5 mg/kg for 12 months, the following were the histological findings. The parathyroids were hyperplastic; the nuclei of chief cells became enlarged (> 5 u) compared with normal (< 5 u) and more vesicular. Subsequently, the chief cells showed vacuolation. The long bones showed cystic cavities and osteoporosis with fractures. Lastly, the parathyroid glands exhibited degenerative changes as if they had been burnt out. Bones showed osteophytes but no osteosclerosis. Apart from this, no ossification of soft tissues - such as ligaments or tendons of the kind seen in human endemic fluorosis- was noted.

Terrestrial Ecology Group Leader, Environmental Science and Engineer Engineering, Inc., Gainesville, Florida and Biologist

Summary: Symptoms of fluorosis described for cattle and other domestic animals appear to be similar for those observed in fluoride-intoxicated deer. A study of fluorosis in black-tailed deer (Odocoileus hemionus columbianus) has revealed that deer exhibit dental and osseous lesions whose severity increases with increasing levels of fluoride in the tissues. The major pathway of fluoride intoxication of the population is through fluoride contaminated browse. Greatest exposure to fluoride occurs during the winter months when browsing is confined to a few plant species with high fluoride levels.

Effects of fluoride intoxication of several months on hemostasis in rabbits in the presence and absence of an antidote (Boron)

Summary: Intoxication of rabbits with 40 mg/kg/day of fluoride during a seven-month period induced a discrete disturbance of hemostasis, and of coagulation. Changes in the global coagulation and prothrombin complex occurred, but formation of fibrin or of platelets appeared normal. Vitamin D and calcium given during three weeks following discontinuence of fluoride normalized the global coagulation but failed to improve the changes in prothrombin complex. Boron added to fluoride in drinking water in doses of 15.4 mg/kg/day throughout the period of intoxication prevented the disturbance of the coagulation.

The interaction of dietary vitamin C, protein and calcium with fluoride toxicity (Fluoride effects and nutritional stress)

Physiological effects of systemic fluoride applications to bean leaves and pea epicotyls

Effect of fluorine and an antidote (Boron) on respiration of liver tissue in rabbits

Elsair J, Merad R, Denine R, Reggabi M, Alamir B, Benali M, Khelfat K, Rachedi MA

Summary: Serum and urinary fluoride levels were studied in 20 mongrel dogs, before and after a challenge of fluoride ions. Levels were higher in experimental animals obtained from areas of proven endemicity compared to controls. However the concentration of fluoride in both serum and urine was much greater in animals from an area where, in the past, fluorosis was proven to be endemic but where drinking water now contains 0.6 ppm fluoride. It is suggested that mobilization of stored skeletal fluoride continues over an extended period of time in response to a reduced fluoride content in water.

Summary: For the evaluation of the phytotoxic effect of floride, no single parameter by itself would be conclusive in litigation. Contrary to the views of some, one cannot obtain an adequate answer in a given situation by evaluating the appeaance of plants in a polluted area in relation to their fluoride content. For the diagnosis, one must include in the investigation a number of other nonfluoride-induced environmental parameters which cause macroscopic appearances of vegetation similar to those due to fluoride. This subject is discussed in this paper with special consideration to the water economy of the plant which is particularly important for its physiological state and for determining the extent of damage.

Department of Medicine, Institute of Medical Sciences, Osmania Medical College, Hyderabad, India

Summary: Urinary fluoride is generally regarded as an index of fluoride ingestion. Urinary fluoride excretion was studied in fifty fluorotic patients living, since birth, in an endemic area. The results were related to the severity of the disease and the duration of exposure. A statistically significant correlation was present between the severity of the disease and the duration of exposure and also between the severity of disease and urinary fluoride excretion. In persons belonging to the same socio-economic status and involved in the same occupation, urinary fluoride levels varied grossly with the duration of exposure.

Summary: Chronic fluoride intoxication in humans and animals can produce four distinct bone diseases: osteosclerosis, osteomalacia, secondary hyperparathyroidism and osteoporosis (partly combined). On the basis of own experience and a review of the literature a theory is presented in an attempt to explain these four contrary findings. According to this theory, the dosage of fluoirde, the deficiency of calcium and vitamin D, differences of species, duration of fluoride intake and individual sensitivity play an important role. Fluoride acts upon three bone constituents: osteoblasts, osteoclast and bone mineral.

Total fluoride intake of infants

As cited and abstracted in Fluoride 1980; 13(1):43-44

L Singer and R Ophaug

In view of the dissenting views in the literature on the maximum safe daily dosage of fluoride in infants up to six months of age, the authors determined the fluoride content of commercially prepared infant foods processed with fluoridated and nonfluoridated water. They obtained samples of the major infant foods and milk formulations and calculated the minimum and maximum total daily fluoirde intake by infants six months old and less.

The fluoride content of these foods was not related consistently to the levels in the water used for processing. Meat products averaged 0.14 to 0.43 ppm fluoride except for chicken, the man fluoride content of which was as high as 5.29 ppm. In vegetables the fluoride levels were between 0.02 to 0.67 ppm. However, in a given vegetable processed at different plants fluoride levels varied up to twentyfold; they were not related to the level of fluoride present in the water used for processing. The average fluoride content of fruits was approximately 0.05 ppm, and considerably less than that in vegetables and in meats.

However, the level of fluoride in the water used in processing dry cereals, fruit juices and milk definitely influenced the produc't fluoride levels. Cereals processed in plants which were using fluoridated water contained approximately 4 to 6 ppm as contrasted with less than one half this amount in cereals prepared in plants using nonfluoridated water. In rice cereal, the highest values were obtained, namely 6.35 ppm, in plants where fluoridated water was used and 2.11 ppm where the water was nonfluoridated. Similarly, when fluoridated water is used in processing fruit juices their fluoride content is increased up to twentyfold.

With respect to milk, commercially prepared formulas prepared with fluoridated water contributed materially to the total daily fluoride intake of infants. Four ready-to-feed milk formulations prepared with fluoridated water contained an average of 0.67 ppm in contrast to an average of only 0.15 ppm in milk processed with nonfluoridated water.

On the basis of these data the authors calculated the total daily fluoride intake by an infant consuming processed food, milk and juices prepared in a fluoridated plant. The total fluoride intake was estimated to be 0.633 mg per day at two months of age and 0.763 at six months or, 0.127 mg/kg at two months and 0.094 mg/kg at six months expressed in terms of mgF/kg of body weight. The higher values for milk formulas may be offset by lower values for vegetables and fruit.

With cereal, milk and fruit juices not prepared with fluoridated water the comparative figures are 0.01 mg/kg at two months 0.015 mg/kg and 0.019 mg/kg at four and six months of age. If ready-to-feed milk formulas processed in a nonfluroidated plant are substituted for human or cows milk the calculated fluoride intake would be approximately 0.025 mg/kg at two, four and six months of age. The authors concluded that use of fluorinated water inprocessing may significantly increase the total fluoride intake of infants up to six months of age.

Caries Res 1979; 13:18-22

Urinary fluoride concentrations in 6-9 year old children drinking water with a very low fluoride level

As cited (and abstracted) in Fluoride 1980; 13(1):45

IL Shannon and DM Sanders

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=524356&dopt=Abstract

The normal levels of fluorine in the bone tissue of Japanese subjects.

Suzuki Y.

The variation of fluorine concentration by sex and age in bones of Japanese subjects was estimated. The subjects had lived in districts virtually with no fluoride in drinking water and air. The rib bone and the iliac crest were selected for investigation. The fluorine concentration in bones was about 100 ppm in dry (fat-free) weight and 200-230 ppm in ash weight from birth to 19 in both sexes, and increased in their twenties, reaching a plateau level in the 60's. The fluorine concentration in rib bones, however, was 610 ppm in dry (fat-free) weight and 1100 ppm in ash weight, which was slightly higher than that in ilia with 530 ppm in dry (fat-free) weight and 960 ppm in ash weight, respectively. The bones of males contained more fluorine than those of females. The concentration of Ca, P and Mg in bone tissue did not correlate with fluorine concentration.

PMID: 524356 [PubMed - indexed for MEDLINE]

Inorganic and organic fluoride concentrations in tissues after the oral administration of sodium monofluoroacetate (Compound 1080) to rats.

Egekeze JO, Oehme FW.

Male rats were used to study the inorganic (ionic) and organic fluoride concentrations in plasma, liver, kidneys and stomach content after oral doses of 0, 2.2, 3.5, 4.0, 5.0 and 7.0 mg sodium monofluoroacetate (SMFA, Compound 1080)/kg body weight. Tissue and plasma ionic fluoride concentrations were observed to be higher in all rats given SMFA as compared to rats in the control group. This observation suggests in vivo defluorination of SMFA. Homogenates of liver obtained from SMFA poisoned rats showed significant increases in ionic fluoride concentration during a 6-day storage period at +4 degrees C, with the total fluoride concentration (ionic and organic) remaining constant. The average percentages of distribution of SMFA (organic fluoride) in plasma, liver, and kidneys were 7.05, 5.07 and 1.68, respectively. Plasma and tissue SMFA concentrations were generally lower than the corresponding stomach fluid SMFA concentrations for all dosage groups. Lethal concentration of SMFA in the liquid stomach content was in the range 84.9--189 micrograms/ml, corresponding to total (ionic and organic) fluoride concentrations in the range of 16.1--36 micrograms/ml.

PMID: 542959 [PubMed - indexed for MEDLINE]

Sodium monofluoroacetate (SMFA, compound 1080): a literature review.

Egekeze JO, Oehme FW.

Publication Types:

[What is fluoroacetate diabetes?]

[Article in German]

Reichelt H.

The opinion is incorrect that the monofluor carbon-induced hyperglucosaemia which in literature is cited under the term fluor acetate diabetes is caused by insulin deficiency due to lesion of the pancreatic beta-cells. The cause of the fluor acetate diabetes is a disturbance of the glucose degradation by inhibition of the enzyme phosphofructokinase. Insulin applications have no causal influence on the monofluor carbon intoxications and no symptomatic influence on the fluor acetate diabetes.

PMID: 160686 [PubMed - indexed for MEDLINE]

Fluoride inhibition of protein synthesis.

Holland RI.

Publication Types: Review

Acute toxicity of methyl fluorosulfonate (Magic Methyl).

Hite M, Rinehart W, Braun W, Peck H.

Methyl fluorosulfonate (Magic Methyl), an active methylating agent used by research chemists, was studied for acute oral toxicity, acute inhalation toxicity, ocular irritation, and dermal irritation. This compound is very hazardous and may have been responsible for at least one human death. The results of these studies confirmed that Magic Methyl is markedly toxic by all routes studied and particularly by the inhalation route since the LC50 value for rats was found to be between 5 and 6 ppm.

PMID: 484483 [PubMed - indexed for MEDLINE]

Effect of sodium fluoride on cyclic AMP production in rat hepatocytes.

Shahed AR, Miller A, Chalker D, Allmann DW.

The effect of NaF on cAMP production was studied in hepatocytes isolated from fed and fasted rats. A four-six fold increase in hepatocyte cAMP production was observed in the presence of 10-20 mM NaF in cells isolated from either fed or fasted rats. The maximal stimulation of cAMP production was observed after a 10 min incubation in the presence of 1 mM theophylline. However, as little as 0.05-0.15 mM NaF induced a significant increase in cAMP production. It was also found that NaF would alter the production of glucose in isolated rat hepatocytes. When hepatocytes from fed rats were incubated with 0.05-5 mM NaF there was an increase in amount of glucose released from endogenous sources. Also NaF resulted in a decrease in lactate and pyruvate production. Similarly NaF stimulated glucose production in hepatocytes from fasted rats. The maximal stimulation was observed with about 0.15-0.25 mM NaF. At NaF concentrations greater than 1.5 mM a decrease in glucose production was observed. It is concluded that NaF increases the level of cAMP and alters glucose metabolism in intact hepatocytes.

PMID: 220288 [PubMed - indexed for MEDLINE]

[Fluorocarbons as blood substitutes. Toxicity in the rat]

[Article in French]

Faradji A, Giunta M, Dayan Y, Foulletier L, Oberling F.

Liquid fluorocarbons, having high solubility for gases (O2, CO2...) have been used as artificial blood substitutes in animals with variable results. The great diversity of these products and the lack of reproductiveness in their composition have not permitted, up to now, a standardization of their utilisation norms. Our work was to study the toxicity, in the rat, of a new kind of fluorocarbon emulsion (E-66, Ugine-Kuhlmann, France) used as an artificial blood substitute during exchange-perfusion. The short survival of the rats is in opposition to the good in vitro results obtained in other experiments (high solubilities of oxygen and dioxide carbon). The toxicity of this fluorinated emulsion is demonstrated by histologic lesions in lungs, liver and kidneys and the great amount of fluor stored in these organs. The mechanism of this toxicity is still to be demonstrated. Hepatic lesions (hyperhemia with dilatation of central veins and sinusoids) and pulmonary lesions (vascular congestion, alveolar oedema) prove a circulatory disturbance leading to right-sided cardiac failure. However, cellular degenerescence lesions, observed in hepatocytes and renal tubular cells, do not permit to exclude formally a cellular toxicity of the E-66 emulsion.

PMID: 472595 [PubMed - indexed for MEDLINE]

[Fluorine in the urine and bones of occupationally exposed workers and non-exposed men]

[Article in German]

Irlweck K, Czitober H, Machata G.

The fluorine concentration (determined by means of fluorine specific electrode) in the urine of occupationally exposed workers in the aluminium industry showed elevated values of 4.8 +/- 2.9 microgram F/ml (arithmetic mean, n = 33). In comparison, non exposed men, aged 14-68 (n = 11), had values of 0.32 +/- 0.21 microgram F/ml urine. Children below the age of 10 a (n = 9) had a significantly lower fluorine concentration of 0.12 +/- 0.07 microgram F/ml urine. A 56 years old man suffering from severe industrial fluorosis showed fluorine concentrations of, 2.5-3.4 microgram F/ml urine. A bone biopsy specimen (iliac crest) taken from this man showed a fluorine concentration of 4320 ppm, which corresponds to a twenty-fold increase of fluorine, compared with controls.

PMID: 547653 [PubMed - indexed for MEDLINE]

Reconsidering the 1975 census of U.S. communities which provide naturally fluoridated waters.

Spears ND.

PMID: 287802 [PubMed - indexed for MEDLINE]

Identification and partial characterization of some components of hormone-stimulated adenylate cyclase.

Ross EM, Howlett AC, Gilman AG.

Adenylate cyclase can be resolved into at least two protein components, neither of which by itself catalyzes the formation of cyclic AMP with Mg-ATP as substrate. Mixture of the two reconstitutes Mg-ATP-dependent, fluoride- and Gpp(NH)p-stimulable activity. One, a heat-labile, N-ethylmaleimide-sensitive protein of molecular weight 190,000 can catalyze cyclic AMP formation with Mn-ATP as substrate, and is therefore proposed to be the catalytic moiety of the adenylate cyclase complex. The other protein (or proteins) is more resistant to heating or N-ethylmaleimide, and is proposed to confer upon the catalyst the ability to ultilize Mg-ATP as substrate. It is also required for the regulation of that activity by guanine nucleotides, hormones, and probably fluoride ion. The catalytic protein is found in a phenotypically adenylate cyclase-deficient (AC-) variant of S49 lymphoma cells. The thermostable regulatory protein can be resolved from the catalyst by heat treatment or N-ethylmaleimide treatment of plasma membranes of wild-type S49 cells, rat or rabbit liver, or avian erythrocytes, and is also found in a phenotypically adenylate cyclase-deficient hepatoma cell line. Mixture of AC- S49 membranes, which contain the beta-adrenergic receptor, with a crude detergent-solubilized preparation of the regulatory protein reconstitutes hormone-stimulable adenylate cyclase activity. Binding of the regulatory protein to the membranes is a time- and temperature-dependent process that requires an activating ligand of the adenylate cyclase system [fluoride, Gpp(NH)p].

PMID: 231786 [PubMed - indexed for MEDLINE]

[Fluorine content in the urine and in the serum of hydrofluoric acid workers as an index of health administration (author's transl)]

[Article in Japanese]

Toyota S.

The behavior of fluoride ion level in the urine and in the serum was measured as an index for health care of workers exposed to hydrofluoric acid, the effect of fluorine-containing foodstuff intake by the workers being considered at the same time. For this study, 250 hydrofluoric acid workers and as a control group 1,600 non-hydrofluoric-acid workers were examined. All workers, ranging in age from 15 to 59 years old, came from the same electronics factory. Fluorides in the biological fluids were measured by using the fluoride ion-specific electrode method and the electrode potential recording method concurrently. The fluoride ion levels (geometric mean) in the urine and in the serum of the non-hydrofluoric-acid workers were determined to be 0.59 ppm and 12 ppb, respectively. Among the influences of fluorine-containing foodstuff on fluoride content in the biological fluids, the effect of black tea and/or green tea intake was particularly remarkable. In the case of the non-hydrofluoric-acid workers, the concentration increased to about double of the control value. Similarly in a diet test on volunteers, the concentration increased about six times. As for the response to tea intake with the lapse of time, the concentration in the urine specimen (spot urine, S.G. corrected: 1.024) reached the maximum value three hours after the intake. In the case of the serum specimen, the maximum value was recorded one hour after the intake, and the influence of the intake continued for several hours. These results suggest that, in the medical examination of hydrofluroic acid workers, restriction of intake of tea and in some cases even a fasting program would have to be introduced as necessary pre-conditions. Upon observation of fluorine concentration in the urine with the lapse of time of hydrofluoric acid workers restricting tea intake, it was confirmed that the trend of the day-to-day variation was small. But that of the in-a-day variation, namely, an increase in the concentration toward the end of daily working hours was obvious. By introduction of these well-regulated methods, it has become possible to properly evaluate even the influence of hydrofluoric acid on the workers irregularly exposed to a hydrofluoric acid environment having a lower concentration than that of the threshold limit value (3 ppm). However, in view of ease of collection and measurement of specimens, speed, and degree of response to the exposure, it can be concluded that the measurement of fluorine content in the urine is more advantageous as an index for the health care than that in the serum. For this reason it is desirable that the former method should be given priority from the view point of prevailing industrial hygiene laws and regulations.

PMID: 537219 [PubMed - indexed for MEDLINE]

No Abstract available

Reconstitution of catecholamine-sensitive adenylate cyclase. Association of a regulatory component of the enzyme with membranes containing the catalytic protein and beta-adrenergic receptors.

Howlett AC, Sternweis PC, Macik BA, Van Arsdale PM, Gilman AG.

PMID: 218930 [PubMed - indexed for MEDLINE]

Effects of phospholipase A2 and filipin on the activation of adenylate cyclase.

Lad PM, Preston MS, Welton AF, Nielsen TB, Rodbell M.

Rat liver plasma membranes were incubated with phospholipase A2 (purified from snake venom) or with filipin, a polyene antibiotic, followed by analysis of the binding of glucagon to receptors, effects of GTP on the glucagon-receptor complex, and the activity and responses of adenylate cyclase to glucagon + GTP, GTP, Gpp(NH)p, and F-. Phospholipase A2 treatment resulted in concomitant lossess of glucagon binding and of activation of cyclase by glucagon + GTP. Greater than 85% of maximal hydrolysis of membrane phospholipids was required before significant effects of phospholipase A2 on receptor binding and activity response to glucagon were observed. The stimulatory effects of Gpp(NH)p or F- remained essentially unaffected even at maximal hydrolysis of phospholipids, whereas the stimulatory effect of GTP was reduced. Detailed analysis of receptor binding indicates that phospholipase A2 treatment affected the affinity but not the number of glucagon receptors. The receptors remain sensitive to the effects of GTP on hormone binding. Filipin also caused marked reduction in activation by glucagon + GTP. However, in contrast to phospholipase A2 treatment, the binding of glucagon to receptors was unaffected. The effect of GTP on the binding process was also not affected. The most sensitive parameter of activity altered by filipin was stimulation by GTP or Gpp(NH)p; basal and fluoride-stimulated activities were least affected. It is concluded from these findings that phospholipase A2 and filipin, as was previously shown with phospholipase C, are valuable tools for differentially affecting the components involved in hormone, guanyl nucleotide, and fluoride action on hepatic adenylate cyclase.

PMID: 420840 [PubMed - indexed for MEDLINE]

Retention by sheep magnesium, phosphorus and fluorine from magnesium and calcium phosphates.

Hemingway RG, McLaughlin AM.

PMID: 487050 [PubMed - indexed for MEDLINE]

Paper presented at the 29th Annual Conference of the Neurological Society of India in Banagalore

A survey of the literature on osteofluorosis reveals little information on the morphological changes of the peripheral nervous system in this disease.

Biopsies of the sural nerve at the ankle level removed from 13 patients with osteofluorosis were studied by conventional methods. In 10 out of the 13 cases, the mean fiber densities (number of fibers/mm2) of the myelinated fibers were reduced, indicative of nerve fiber loss. In about half of the cases there was a decrease in the number of the fibers of small size (< 7um). A very poor correlation between the internodal lengths and internodal diameters, found in 7 of these patients, suggested a process of demyelination and remyelination. The presence of other features such as irregularities and wrinkling of myelin and considerable variation in the diameters within the internodes are suggestive of axonal damage as well.

Excerpt: ... The source of fluoride in the carpenter's establishment was sawdust in his work area which contained 24% fluorine, present in chromium trifluoride was used to impregnate large roof beams. It was believed that the dogs' food became contaminated with the sawdust. Another source of fluoride intake in dogs is commercial dog food, samples of which contained between 4.5 to 80.4 ppm of fluoride dry weight.

Table 1 Comparative Toxicological and Differential Dagnostic Data to Dogs
	Sodium Fluoroacetate (FAC)	Strychnine Poisoning
Oral Toxicty (mg/kg)	0.06-0.2	0.75
Pathogenesis	Blocking of aconitase	Blocking of spinal cord reflex arch.
Metabolism	"Lethal synthesis" of fluorocitrate	Possible detoxification (oxidation) in liver
Latency	Relatively long (most often over 4 hrs., sometimes 24 hrs.	Relatively short (between minutes to 2 hrs.)
Secondary poisoning	Possible	Possible
Clinical signs	Restlessness; wild running; barking; vomiting; defaecation; urination; intermittent tetanic seizures with opistotonus.	Nervousness; restlessness; hypersensitivity to external stimuli; spasms; opisthotonus; retraction of lips; auricular stiffness; cyanosis
Post-mortem Findings	General cyanosis; hepatic congestion; often empty stomach; colon and urinary bladder; pulmonary edema; frothy muscus in the trachea and bronchi; diffuse gastric mucosal congestion; hemorrhages in the thymus and pancreas.	Venus congestion; usually full stomach; hemorrhages in the thymus and pancreas.
Treatment	Futile. - Specific antidotes (acetate donors) may prevent poisoning only.	Maintenance of relaxation and prevention of asphyxia. For relaxation, pentobarbital or methocarbamol.