Reproductive - Adverse Effects
Sodium fluoride
CAS No. 7681-49-4

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• Note: The following is a limited selection of abstracts from 1994 to present.
• Due to length, we present this as a separate section
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1997. A dissertation submitted to the School of Biological Sciences, University of Surrey, in fulfilment of the requirements for the Degree of Doctor of Philosophy. Guildford 1997.
The effect of fluoride on the physiology of the pinal gland
Jennifer Anne Luke

The purpose was to discover whether fluoride (F) accumulates in the pineal gland and thereby affects pineal physiology during early development. The [F] of 11 aged human pineals and corresponding muscle were determined using the F-electrode following HMDS/acid diffusion. The mean [F] of pineal was significantly higher (p<0.001) than muscle: 296 ± 257 vs. 0.5 ± 0.4 mg/kg respectively. Secondly, a controlled longitudinal experimental study was carried out to discover whether F affects the biosynthesis of melatonin, (MT), during pubertal development using the excretion rate of urinary 6-sulphatoxymelatonin, (aMT6s), as the index of pineal MT synthesis. Urine was collected at 3-hourly intervals over 48 hours from two groups of gerbils (Meriones unguiculatus), low-F (LF) and high-F (HF) (12 f, 12 m/group): under LD: 12 12, from prepubescence to reproductive maturity (at 9-12 weeks) to adulthood, i.e., at 7, 9, 11 1/2 and 16 weeks. The HF pups received 2.3 ug F/g BW/day from birth until 24 days whereafter HF and LF groups received food containing 37 and 7 mg F/kg respectively and distilled water. Urinary aMT6s levels were measured by radioimmunoassay. The HF group excreted significantly less aMT6s than the F group until the age of sexual maturation. At 11 1/2 weeks, the circadian profile of aMT6s by the HF males was significantly dimished but, by 16 weeks, was equivalent to the LF males. In conclusion, F inhibits pineal MT synthesis in gerbils up until the time of sexual maturation. Finally, F was associated with a significant acceleration of pubertal development in female gerbils using body weights, age of vaginal opening and accelerated development of the ventral gland. At 16 weeks, the mean testes weight of HF males was significantly less (p<0.002) than that of the LF males. The results suggest that F is associated with low circulating levels of MT and this leads to an accelerated sexual maturation in female gerbils. The results strengthen the hypothesis that the pineal has a role in pubertal development.

Excerpt on the Newburgh-Kingston NY study:

To the best of my knowledge, the Newburgh-Kingston study is the only reference on the efffect of F on the timing of puberty in humans. It is the largest, most ambitious paediatric survey carried out to demonstrate the safety of water fluoridation. The New York State Department of Health initiated the study in 1944 because they realized that there would ultimately be a need for a long-term evaluation of any possible systemic effects as well as the dental changes from drinking fluoridated water over a long period of time.

Similar groups of chidren were selected for long-term observation from Newburgh (fluoridated to 1.0 to 1.2 mg/L in 1945) and Kingston (essentially F-free for the duration of the study). Newburgh and Kingston were chosen because they were well-matched: both situated on the Hudson River about 35 miles apart with similar upland reservoir water supplies; both had populations of about 30,000 with similar demographic characteristics, social and economic conditions, levels of dental care, etc. In Newburgh, out of 817 children (aged from birth to nine years) who were selected in 1945, 500 were examined in 1954-1955; in Kingston, out of 711 children who were selected in 945, 405 were examined in 1954-55.

The medical and dental examinations began in 1944, and were repeated periodically until 1955. An assessment of any possible systemic effects arising from the consumption of fluoridated water was made by comparing the growth, development and the prevalence of specific conditions in the two groups of children as disclosed by their medical histories, physical examinations, and laboratory and radiological evidence. The age of onset of menstruation in girls was used as an index of the rate of sexual maturation.

At the end of ten years, the investigators repored no adverse systemic effects from drinking fluoridated water because no significant differences were found between the results from the two groups. The average age of first menarche was earlier among girls in Newburgh than those in Kingston: 12 years vs. 12 years and 5 months respectively (Schlesinger et al, 1956). Although this difference was not considered important, it does suggest an association between the use of fluoridated drinking water and an ealier onset of sexual maturation in girls. The Newburgh girls had not had a lifelong use of fluoridated water. For the first two years or so, they received unfluoridated water. Furthermore, their only source of F was from the drinking water. (pages 6-7)."

• Note from EC: Excerpts are from the hard copy of Luke's thesis. Any spelling errors are mine.

Artificial water fluoridation causes fluoride poisoning in horses.

Lennart Krook

Professor of Pathology, Emeritus. Cornell Veterinary Medicine.

A community in Colorado fluoridated the water some 20 years ago in a concentration of 1.3 parts per million (ranging from 0.35 to 1.35). For a local Quarter Horse operation, from 6 to 10 horses, this was the only source of water. There were no phosphate fertilizer used or any phosphate supplements for the horses. Signs of fluoride poisoning started to appear after five years and included interference with reproduction, crooked leg bones. Blood analyses showed decreased levels of thyroid gland hormone. Post-mortem examination of cannon-bones revealed pile-up of bone tissue on the inner surface (endostosis) and chemical analysis of dried bone confirmed the diagnosis of chronic dental fluorosis which grew worse with time and finally showed severe destruction of tooth-supporting bone. Over the years, 5 horses were killed because of progressive signs of chronic fluoride poisoning.

Ref: J Toxicol Clin Toxicol 1996;34(2):183-9.

Circulating testosterone levels in skeletal fluorosis patients.

Susheela AK, Jethanandani P.

Fluoride and Fluorosis Research Laboratories, All India Institute of Medical Sciences, New Delhi, India.

OBJECTIVE: The present study focuses on serum testosterone concentrations in patients with skeletal fluorosis, in order to assess the hormonal status in fluoride toxicity.
METHODS: Serum testosterones were compared for patients afflicted with skeletal fluorosis (n = 30) and healthy males consuming water containing less than 1 ppm fluoride (Control 1, n = 26) and a second category of controls (Control 2, n = 16): individuals living in the same house as the patients and consuming same water as patients but not exhibiting clinical manifestations of skeletal fluorosis.
RESULTS: Circulating serum testosterones in skeletal fluorosis patients were significantly lower than those of Control 1 at p < 0.01. Testosterone concentrations of Control 2 were also lower than those of Control 1 at p < 0.05 but were higher than those of the patient group.
CONCLUSIONS: Decreased testosterone concentrations in skeletal fluorosis patients and in males drinking the same water as the patients but with no clinical manifestations of the disease compared with those of normal, healthy males living in areas nonendemic for fluorosis suggest that fluoride toxicity may cause adverse effects in the reproductive system of males living in fluorosis endemic areas.

PMID: 8618252 [PubMed - indexed for MEDLINE]

Int J Fertil Menopausal Stud 1994 May-Jun;39(3):164-71

Ultrastructural studies of spermiogenesis in rabbit exposed to chronic fluoride toxicity.

Kumar A, Susheela AK

Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.

OBJECTIVE--To address the role of fluoride in causing defects to spermatids and epididymal spermatozoa.
METHODS--Male rabbits were treated with 10 mg NaF/kg body weight daily for 18 months and maintained under identical laboratory conditions along with the control rabbits not given NaF. Testis and epididymis (caput) were investigated for ultrastructural details of spermatids and spermatozoa.
RESULTS--A wide variety of structural defects were observed in the flagellum, the acrosome, and the nucleus of the spermatids and epididymal spermatozoa of fluoride-treated rabbits. Abnormalities included absence of outer microtubules, complete absence of axonemes, structural and numeric aberrations of outer dense fibers, breakdown of the fibrous sheath, and structural defects in the mitochondria of the middle piece of the flagellum. Detachment and peeling off of the acrosome from the flat surfaces of the nucleus were also observed.
CONCLUSION--The abnormalities observed render the sperm nonfunctional and ineffective, and thus there is a possible role of fluoride in causing infertility.

PMID: 7920753 [PubMed - indexed for MEDLINE]

Reprod Toxicol 1994 Mar-Apr;8(2):155-9.

In vitro fluoride toxicity in human spermatozoa.

Chinoy NJ, Narayana MV

Department of Zoology, School of Sciences, Gujarat University, Ahmedabad, India.

Abstract: Effects of sodium fluoride (NaF) on washed, ejaculated human spermatozoa at doses of 25, 50, and 250 mM were investigated in vitro at intervals of 5, 10, and 20 min. Sodium fluoride (NaF) did not affect the extracellular pH of sperm, except that a slight acidification was caused by the 250 mM dose only. The treatment caused a significant enhancement in acid phosphatase (ACPase) and hyaluronidase activities after 5 and 10 min. However, the decrease in the lysosomal enzyme activity after 20 min treatment could have been due to the gradual increase in fluoride accumulation by spermatozoa leading to membrane damage. Silver nitrate staining of sperm revealed elongated heads, deflagellation, and loss of the acrosome together with coiling of the tail. Sperm glutathione levels also showed a time-dependent decrease with complete depletion after 20 min indicating rapid glutathione oxidation in detoxification of the NaF. The altered lysosomal enzyme activity and glutathione levels together with morphologic anomalies resulted in a significant decline in sperm motility with an effective dose of 250 mM.

PMID: 8032126 [PubMed - indexed for MEDLINE]

Reprod Toxicol 1991;5(6):505-12

Microdose vasal injection of sodium fluoride in the rat.

Chinoy NJ, Rao MV, Narayana MV, Neelakanta E

Department of Zoology, University School of Sciences, Gujarat University, Ahamadabad, India.

Abstract: A single microdose (50 micrograms/50 microL) injection of sodium fluoride (NaF) into the vasa deferentia of adult male albino rats (Rattus norvegicus) caused arrest of spermatogenesis and absence of spermatozoa in the lumina of the seminiferous tubules of the testes, which consequently led to a decline in the sperm count in the caudae epididymides. Scanning electron microscopy of cauda and vas deferens sperm revealed deflagellation and tail abnormalities. This is probably related to the alterations in the internal milieu of these organs which rendered the spermatozoa immotile and consequently caused fertility impairment in the experimental animals. Thus microdoses of sodium fluoride were found to affect reproductive function and fertility rate.

PMID: 1839778 [PubMed - indexed for MEDLINE]

Environ Res. 2003 Sep;93(1):20-30.

Fluoride-induced disruption of reproductive hormones in men.

Ortiz-Perez D, Rodriguez-Martinez M, Martinez F, Borja-Aburto VH, Castelo J, Grimaldo JI, de la Cruz E, Carrizales L, Diaz-Barriga F.

Laboratorio de Toxicologia Ambiental, Facultad de Medicina, Universidad Autonoma de San Luis Potosi, Av. Venustiano Carranza 2405, Col. Lomas Filtros, CP 78210, San Luis Potosi, Mexico.

Abstract: Fluoride-induced reproductive effects have been reported in experimental models and in humans. However, these effects were found in heavily exposed scenarios. Therefore, in this work our objective was to study reproductive parameters in a population exposed to fluoride at doses of 3-27mg/day (high-fluoride-exposed group-HFEG). Urinary fluoride levels, semen parameters, and reproductive hormones in serum (LH, FSH, estradiol, prolactin, inhibin-B, free and total testosterone) were measured. Results were compared with a group of individuals exposed to fluoride at lower doses: 2-13mg/day (low-fluoride-exposed group-LFEG). A significant increase in FSH (P<0.05) and a reduction of inhibin-B, free testosterone, and prolactin in serum (P<0.05) were noticed in the HFEG. When HFEG was compared to LFEG, a decreased sensitivity was found in the FSH response to inhibin-B (P<0.05). A significant negative partial correlation was observed between urinary fluoride and serum levels of inhibin-B (r=-0.333, P=0.028) in LFEG. Furthermore, a significant partial correlation was observed between a chronic exposure index for fluoride and the serum concentrations of inhibin-B (r=-0.163, P=0.037) in HFEG. No abnormalities were found in the semen parameters studied in the present work, neither in the HFEG, nor in the LFEG. The results obtained indicate that a fluoride exposure of 3-27mg/day induces a subclinical reproductive effect that can be explained by a fluoride-induced toxic effect in both Sertoli cells and gonadotrophs.

PMID: 12865044 [PubMed - indexed for MEDLINE]

Full report available at:

Fluoride 2000; 33(3):128-134.

Fertility effects of sodium fluoride in male mice

Ahmed Elbetieha, Homa Darmani, Ahmad S Al-Hiyasat.

Abstract: SUMMARY. Sexually mature male Swiss mice were exposed at 60 days of age to 100, 200 and 300 ppm sodium fluoride (NaF) in their drinking water for 4 weeks or 10 weeks. The effect of NaF exposure on fertility was assessed by breeding these males with untreated female mice after the exposure periods. Fertility was significantly reduced at all three concentrations by exposure for 10 weeks but not for 4 weeks. The number of implantation sites and viable fetuses was significantly reduced in females mated with males that had ingested NaF at a concentration of 200 ppm for 10 weeks. Relative weights of seminal vesicles and preputial glands were significantly increased in mice exposed to 200 and 300 ppm NaF for 4 weeks but not in mice exposed for 10 weeks. These results indicate that long-term ingestion of NaF adversely affects fertility in male mice.

Dart Special at Toxnet

Chung-Kuo Kung Kung Wei Sheng (China Public Health) 2000 Aug;16(8):697-8

[The primary study of antagonism of selenium on fluoride-induced reproductive toxicity of male rat]

Zhu XZ et al.

Abstract: The protective effect of ascorbic acid at dose level of 1.0 mg/L in drinking water against the fluoride-induced damage on reproductive system of rat was studied. 150 mg/L sodium fluoride (NaF) in drinking water of male rat can cause the significant decrease of sperm count and mobility, the increase of serum and testicular lipid peroxides (LPO) contents, and the adenosine triphosphatase (ATPase) activity depression of epididymis. All of those effects are reversible by adding adequate ascorbic acid in drinking water simultaneously. The effects of ascorbic acid against fluoride-induced damages are similar to those produced by 2.0 mg/L Na2SeO3 in the drinking water of rats. However, no significant recovery of fluoride-induced effects on GSH-Px activities in the tissues of testis and epididymis were observed in ascorbic acid and fluoride group. The mechanism of ascorbic acid on fluoride-induced damage of male reproductive system need to be further studied.

Dart Special at Toxnet

Environmental Sciences: an International Journal of Environmental Physiology and Toxicology. 2000; 7(1):29-38

Reversal of fluoride-induced alteration in cauda epididymal spermatozoa and fertility impairment in male mice.

Chinoy NJ and Sharma A

Abstract: The effects of sodium fluoride (NaF) ingestion (10 mg NaF/kg body weight) and the possible therapeutic effects of ascorbic acid (AA, 15 mg/animal/day) and/or calcium phosphate (Ca, 25 mg/animal/day) on the reproductive functions and fertility of male mice were investigated. NaF-ingestion brought about a significant decline in sperm acrosomal acrosin and hyaluronidase. Cauda epididymal sperm stained with alcoholic acidic silver nitrate reagent revealed acrosomal damage and deflagellation. However, sperm nuclear integrity was not affected by the treatment. The reduced activity of the enzymes as well as the structural and metabolic alterations in the sperm led to a significant decrease in sperm count, and motility and live:dead ratios but an increase in abnormal sperm which ultimately lead to a poor fertility rate. The cessation of NaF-treatment was not conducive to bringing about a complete recovery. However, the administration of AA or Ca to NaF-treated mice revealed significant recovery from fluoride toxicity in all the above parameters. The recovery was more pronounced in the animal group treated with both AA and calcium in combination, thus indicating a synergistic or additive action. It is concluded that fluoride has a definite effect on male reproduction and fertility. However, the effects are transient and reversible with the administration of AA and Ca. Therefore, AA and Ca are proposed as therapeutic agents for populations in endemic areas for the amelioration of fluoride effects on reproductive functions.

Full report available at

Fluoride 1998; 31(4):203-216.

Amelioration of fluoride toxicity by Vitamins E and D in reproductive functions of male mice

NJ Chinoy and A Sharma.

Abstract: SUMMARY. Studies on the beneficial effects of vitamins E and D supplementation on functions of caput and cauda epididymides, their spermatozoa, vas deferens and seminal vesicle of sodium fluoride (NaF) treated (10 mg/kg body weight) male mice (Mus musculus) were carried out. The NaF treatment resulted in significant decrease in the body and epididymis weight but those of vas deferens and seminal vesicle were not affected. NaF treatment brought about alterations in epididymal milieu as elucidated by the significant decrease in levels of sialic acid and protein as well as activity of ATPase in epididymides. As a result, the sperm maturation process was affected leading to a significant decline in cauda epididymal sperm motility and viability. This caused a significant reduction in fertility rate. The cauda epididymal sperm count was also significantly reduced. The data obtained suggest that fluoride treatment induced significant metabolic alterations in the epididymides, vas deferens and seminal vesicles of mice. The withdrawal of NaF treatment (30 days) produced incomplete recovery. On the other hand, supplementation of vitamins E or D during the withdrawal period of NaF treated mice was found to be very beneficial in recovery of all NaF induced effects, thus elucidating their ameliorative role in recovery from toxic effects of NaF on the reproductive functions and fertility. On the whole, a combination of vitamins E and D treatment was comparatively more effective than that with vitamin E or D alone. Therefore, vitamin therapy could be beneficial for the amelioration of fluoride induced changes in reproductive functions.

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