Fluoride Excretion Research Articles

Tissue distribution, metabolism, and elimination of perfluorooctanoic acid in male and female rats

The elimination, tissue distribution, and metabolism of [1-14C]perfluorooctanoic acid (PFOA) was examined in male and female rats for 28 days after a single ip dose (9.4 mumol/kg, 4 mg/kg). A sex difference in urinary elimination of PFOA-derived 14C was observed. Female rats eliminated PFOA-derived radioactivity rapidly in the urine with 91% of the dose being excreted in the first 24 hr. In the same period, male rats eliminated only 6% of the administered 14C in the urine. The sex-related difference in urinary elimination resulted in the observed difference in the whole-body elimination half-life (t1/2) of PFOA in males (t1/2 = 15 days) and females (t1/2 less than 1 day). Analysis of PFOA-derived 14C in tissues showed that the liver and plasma of male rats and the liver, plasma, and kidney of female rats were the primary tissues of distribution. The relatively high concentration of PFOA in the male liver was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that 11% of the PFOA infused was extracted by the liver in a single pass. The ability of the liver to eliminate PFOA into bile was examined in rats whose renal pedicles were ligated to alleviate sex differences in the urinary excretion of PFOA. In a 6-hr period following IP administration of PFOA, there was no apparent difference in biliary excretion, where both males and females eliminated less than 1% of the PFOA dose via this route. We hypothesized that the sex difference in the persistence of PFOA was due to a more rapid formation of a PFOA-containing lipid (i.e., a PFOA-containing mono-, di-, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid) in the male rat. Also, the increased urinary elimination of PFOA in females may have been due to increased metabolism to a PFOA-glucuronide or sulfate ester. However, no evidence that PFOA is conjugated to form a persistent hybrid lipid was obtained, nor were polar metabolites of PFOA in urine or bile detected. In addition, daily urinary excretion of fluoride in male and female rats before or after PFOA treatment were similar, suggesting that the parent compound is not defluorinated. Thus, the more rapid elimination of PFOA from female rats is not due to formation of a PFOA metabolite.

Dose-related sevoflurane metabolism to inorganic fluoride in rabbits.

Serum concentrations and urinary excretion of inorganic fluoride (fluoride ion), a metabolite of sevoflurane, were measured by an ion-chromatographic analyzer after inhalation of three different concentrations of sevoflurane in adult, male Japanese white rabbits weighing 2.6-3.6 kg. Sevoflurane was administered at concentrations of 0% (control), 1%, 2% and 3% (Groups I, II, III and IV, respectively) through a sevoflurane vaporizer for 2 hr under controlled ventilation. Blood and urine samples were collected during and after termination of sevoflurane inhalation at scheduled time intervals for 24 hr. The total volume of urine, the urinary pH and the osmolality of serum and urine were not significantly different among any of the groups. Osmolality of the serum and urine was within normal range in all groups of animals. The mean serum peak values of fluoride ion were 0.7 +/- 0.5, 22.8 +/- 8.7, 31.8 +/- 11.0 and 41.5 +/- 13.2 microM (mean +/- SD) in groups I, II, III and IV, respectively. Peak values were recorded within 15 min after the termination of inhalation. The cumulative amounts of fluoride ion excreted in urine in 24 hr were calculated to be 5.0 +/- 1.6, 26.1 +/- 6.7, 41.4 +/- 11.3 and 64.3 +/- 18.0 mumol (mean +/- SD) in groups I, II, III and IV, respectively. Regression analysis revealed significant correlations between the formation and excretion of fluoride ion, and the dose of sevoflurane (r = 0.85, p less than 0.05 and r = 0.89, p less than 0.05, respectively). The authors conclude that the formation and excretion of fluoride ion after sevoflurane anesthesia is dependent on the dose of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of perfluorodecanoic acid in male and female rats

The elimination, tissue distribution, and metabolism of [1- 14C]PFDA were examined in male and female rats for 28 days after a single ip dose (9.4 μmol/kg, 5 mg/kg). A sex difference in the fecal elimination of perfluorodecanoic acid (PFDA) was observed with 51 and 24% of the administered 14C being recovered in the feces of male and female rats, respectively, by 28 days post-treatment. The cumulative excretion of PFDA-derived 14C in the urine in 28 days was less than 5% of the administered dose in both sexes. The sex-related difference in the rate of fecal elimination resulted in the observed difference in whole body elimination t 1 2 of PFDA in males ( t 1 2 = 23 days ) and females ( t 1 2 = 45 days ). The liver contained the highest concentration of PFDA-derived 14C in both males and females, followed by the plasma and kidneys. The heart, fat pads, testes, and gastrocnemius muscle of males, and the ovaries of females contained much lower concentrations of PFDA. The reason for the high percentage of the ip dose of [1- 14C]PFDA in the liver (53% males and 41% females, 2 hr post-treatment) was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that approximately 25% of the [ 14C]PFDA in the perfusate was extracted by the liver in a single pass. The basis for the sex difference in fecal elimination of PFDA does not appear to be due to a sex difference in biliary excretion. In a 6-hr period, male and female rats with kidneys ligated ȩliminated essentially the same percentage dose of [ 14C]PFDA into bile. We had hypothesized that the persistence of PFDA in rats was due to formation of a PFDA-containing lipid (i.e., a [ 14C]PFDA-containing mono-, di-, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid). However, no evidence that PFDA is conjugated to form persistent hybrid lipids was obtained, nor were polar metabolites of PFDA detected in urine or bile. In addition, daily urinary excretion of fluoride in male and female rats before and after PFDA treatment was similar, suggesting that the parent compound is not defluorinated. Thus, the disposition of PFDA in male and female rats is characterized by an apparent lack of biotransformation.

Halothane Metabolism in Children

SUMMARY Halothane (1% v/v inspired) was administered for 60 min to six children of mean age 74 months (range 14–119 months). Uptake of halothane was measured from the difference in the concentration in inspired and expired gas and varied from 176 to 310 mg kg−1, depending on minute ventilation. After administration of halothane ceased, its elimination in expired gas was measured in four patients until the conclusion of anaesthesia; 32–37% of the absorbed halothane was expired 90 min after halothane administration ceased. Urinary excretion of trifluoro-acetic acid, fluoride and bromide was measured for up to 1 week. Of the absorbed halothane, 11.4% (range 6.3–18.2%) was excreted in urine as trifluoroacetic acid and 0.37% (range 0.10–0.64%) as inorganic fluoride. The urinary half-life of trifluoracetic acid was 41.8 h (range 10.4–59.1 h). The quantitative and qualitative metabolism of halothane via the reductive and oxidative pathways in children are comparable to values found in adults. No differences in the metabolism of halothane by children were found which would explain the different incidence of halothane-associated hepatitis compared with adults.

Subchronic inhalation study with vinyl fluoride: Effects on hepatic cell proliferation and urinary fluoride excretion

Vinyl fluoride is used widely in the manufacture of fluoropolymers. Based in part on the structural similarity of vinyl fluoride to the hepatocarcinogens vinyl chloride and vinyl bromide, a TSCA Section 4 test rule mandated the testing of vinyl fluoride for oncogenicity. This report presents the results of a 90-day inhalation study in rats and mice with vinyl fluoride designed to set test concentrations for a subsequent oncogenicity study. Groups of 15 male and female rats and mice were exposed 6 hr per day, 5 days per week for approximately 90 days to target concentrations of 0, 200, 2000, or 20,000 ppm vinyl fluoride. Clinical chemical, hematological, and urine analyses were performed on rats after 45 and 90 days of exposure. A hematological evaluation was performed on mice following 45 and 90 days of exposure. A complete gross and microscopic evaluation was conducted at the end of the study. After 93 days on test, groups of five rats and five mice per sex were implanted with osmotic minipumps containing [ 3H]thymidine and were exposed for an additional 5 days to measure cell proliferation in liver, kidney, lung, and nasal cavity tissues. Results of the histopathological, clinical chemical, and hematological evaluations showed no significant effects of vinyl fluoride exposure at any concentration following either 45 or 90 days of exposure. A concentration-related increase in fluoride ion in urine was observed in rats at 45 and 90 days of exposure. A plateau in urinary fluoride excretion was observed at approximately 2000 ppm, suggesting saturation of vinyl fluoride metabolism. Vinyl fluoride-related cell proliferation effects were largely restricted to liver. Hepatic cell proliferation in male and female rats and mice was elevated at all concentrations. The response was similar at concentrations of either 2000 or 20,000 ppm and was consistent with concentration-response relationships for other haloethylenes. Taken together, the urinary fluoride excretion and hepatic cell proliferation data suggest a mechanistic link between the two effects. On the basis of these findings and experience with other haloethylenes, concentrations of vinyl fluoride to be tested for oncogenicity should be chosen such that the full linear range of the concentration-response curve is evaluated. The present study demonstrates through example the value of incorporating cell proliferation studies in standard testing protocols.

HALOTHANE METABOLISM IN CHILDREN

Halothane (1% v/v inspired) was administered for 60 min to six children of mean age 74 months (range 14-119 months). Uptake of halothane was measured from the difference in the concentration in inspired and expired gas and varied from 176 to 310 mg kg-1, depending on minute ventilation. After administration of halothane ceased, its elimination in expired gas was measured in four patients until the conclusion of anaesthesia; 32-37% of the absorbed halothane was expired 90 min after halothane administration ceased. Urinary excretion of trifluoroacetic acid, fluoride and bromide was measured for up to 1 week. Of the absorbed halothane, 11.4% (range 6.3-18.2%) was excreted in urine as trifluoroacetic acid and 0.37% (range 0.10-0.64%) as inorganic fluoride. The urinary half-life of trifluoracetic acid was 41.8 h (range 10.4-59.1 h). The quantitative and qualitative metabolism of halothane via the reductive and oxidative pathways in children are comparable to values found in adults. No differences in the metabolism of halothane by children were found which would explain the different incidence of halothane-associated hepatitis compared with adults.

Journal of Bone and Mineral Research

In this study, the relationship between fluoride pharmacokinetics and the response in spinal bone density to fluoride treatment was studied in 14 patients with primary osteoporosis treated with fluoride for at least 1 year. Serum concentrations and urinary excretion of fluoride were determined after ingestion of 10 mg fluoride as monofluorophosphate. The pharmacokinetic parameters were calculated according to a linear one-compartment open model. The fasting serum fluoride level was 8.8 +/- 0.98 mumol/liter. The peak serum fluoride level was 20.5 +/- 1.4 mumol/liter and was reached within 2 h after ingestion of fluoride. When the patients were divided into good and poor responders, based on whether they did or did not exhibit a change in spinal bone density of 13 mg/cc per year or more, we found that good responders had decreased renal fluoride clearance (-62 +/- 13%, p less than .02), increased maximum change in serum fluoride (+38 +/- 18%, p less than .01), increased extrarenal clearance (+62 +/- 57%, p less than .05) and increased change in serum alkaline phosphatase (ALP) (+241 +/- 169%, p less than 0.02) compared with poor responders. Our data suggest that one factor accounting for a good response is a relatively high serum level of fluoride. However, although the maximum change in serum fluoride was greater in good responders compared with poor responders, variations in fluoride levels could not explain all of the variation in spinal bone density. Therefore, we propose that in addition to differences in serum fluoride, other factors are also responsible for the good response.

Journal of Bone and Mineral Research

The aim of the study was to investigate the usefulness of urinary fluoride excretion in evaluating fluoride therapy. In a prospective study, 35 patients with osteoporosis were treated for about 44 months with a mean dosage of 31.4 mg fluoride ion per day. Urinary fluoride excretion and serum alkaline phosphatase activity were measured at 3-month intervals. Bone mineral content (BMC) was measured in L2-L4 with dual-photon absorptiometer. The mean number of BMC measurements was 5.7 per patient. The interindividual reproducibility for measurements in 10 patients was 2.1%. For each individual, the regression coefficient of BMC for the period of treatment was calculated. Responders were defined as those who had a positive value and nonresponders had 0 or a negative value. The percentage responders was 83%. Between responders and nonresponders no differences were found for age, fluoride dosage, duration of treatment, or changes in serum alkaline phosphatase activity. Urinary fluoride excretion was higher in responders than in nonresponders (p less than 0.001) and a positive correlation (p less than 0.001) was obtained between the changes in BMC and urinary fluoride excretion. In the responders, 90% had a urinary fluoride excretion greater than 8 mg/24 h. All nonresponders had a urinary fluoride excretion less than 8 mg/24 h. Urinary fluoride excretion is a valuable predictor of BMC response during fluoride therapy for osteoporosis.

Computer simulation of oral fluoride clearance

The presence of fluoride in saliva and dental plaque is important for prevention of dental caries. The elimination of fluoride from the oral cavity after introduction of a fluoride containing agent is a complicated physiological process. This process was simulated with a Pascal program running under MS-DOS on IBM-compatible microcomputers. The program calculated the fluoride concentration in saliva as a function of time from several input parameters, the most important being the amount of fluoride, salivary stimulation due to the fluoride vehicle, resting salivary flow rate and volume factors. Furthermore, factors such as excretion of fluoride in the saliva following fluoride absorption in the intestinal tract were modeled. The fluoride concentration in dental plaque due to diffusion was also calculated. Output was directed to files which could be processed by a graphics interface. The results of the computations were very similar to findings in vivo.

The Determination of the Repeated Oral Toxicity of Halocarbon Oil, Series 27-S

Halocarbon 27-S (HC 27-S), a polymer of chlorotrifluoroethylene (CTFE), is used as a lubricating oil for pumps in hyperbaric chambers. Although monomeric CTFE has been shown to produce renal lesions in rats, the toxicity of CTFE polymers have not been investigated. To assess the toxicity of repeated exposure to HC 27-S, three groups (N = 6/group) of male and female Fischer-344 rats were dosed with 2.5 g HC 27-S/kg for 7 or 21 consecutive days. Groups were sacrificed at 7, 21, and 35 days (14 days after the 21-day dosing). Corresponding control groups (N = 6) were dosed with deionized water. Decreased water consumption and urine output were apparent in all test groups. Statistically significant increases in fluoride excretion were noted in 24-hr urine samples assessed periodically during the study. Neurotoxic signs were observed in female rats but not in male rats. Significant increases in liver and kidney weights were seen in all rats, regardless of number of dosing days. The increased fluoride burden in treated animals appeared sufficient to alter bone calcium/phosphate ratios in male rats but not female rats. Gross liver enlargement and hepatocellular cytomegaly indicated that the liver was probably the primary target organ following repeated administration of HC 27-S.

Subchronic Inhalation Study with Vinyl Fluoride: Effects on Hepatic Cell Proliferation and Urinary Fluoride Excretion

Subchronic Inhalation Study with Vinyl Fluoride: Effects on Hepatic Cell Proliferation and Urinary Fluoride Excretion. BOGDANFFY, M. S., KEE, C. R., KELLY, D. P., CARAKOSTAS, M. C, AND SYKES, G. P. (1990). Fundam Appl Toxicol. 15, 394/406. Vinyl fluoride is used widely in the manufacture of fluoropolymers. Based in part on the structural similarity of vinyl fluoride to the hepatocarcinogens vinyl chloride and vinyl bromide, a TSCA Section 4 test rule mandated the testing of vinyl fluoride for oncogenicity. This report presents the results of a 90-day inhalation study in rats and mice with vinyl fluoride designed to set test concentrations for a subsequent oncogenicity study. Groups of 15 male and female rats and mice were exposed 6 hr per day, 5 days per week for approximately 90 days to target concentrations of 0, 200, 2000, or 20,000 ppm vinyl fluoride. Clinical chemical, hematological, and urine analyses were performed on rats after 45 and 90 days of exposure. A hematological evaluation was performed on mice following 45 and 90 days of exposure. A complete gross and microscopic evaluation was conducted at the end of the study. After 93 days on test, groups of five rats and five mice per sex were implanted with osmotic minipumps containing [3H]thymidine and were exposed for an additional 5 days to measure cell proliferation in liver, kidney, lung, and nasal cavity tissues. Results of the histopathological, clinical chemical, and hematological evaluations showed no significant effects of vinyl fluoride exposure at any concentration following either 45 or 90 days of exposure. A concentration-related increase in fluoride ion in urine was observed in rats at 45 and 90 days of exposure. A plateau in urinary fluoride excretion was observed at approximately 2000 ppm, suggesting saturation of vinyl fluoride metabolism. Vinyl fluoride-related cell proliferation effects were largely restricted to liver. Hepatic cell proliferation in male and female rats and mice was elevated at all concentrations. The response was similar at concentrations of either 2000 or 20,000 ppm and was consistent with concentration-response relationships for other haloethylenes. Taken together, the urinary fluoride excretion and hepatic cell proliferation data suggest a mechanistic link between the two effects. On the basis of these findings and experience with other haloethylenes, concentrations of vinyl fluoride to be tested for oncogenicity should be chosen such that the full linear range of the concentration-response curve is evaluated. The present study demonstrates through example the value of incorporating cell proliferation studies in standard testing protocols

5 Occupational skeletal fluorosis

A 20-30 years' occupational and/or environmental exposure to fluorine may cause osteosclerosis, especially of the spine and pelvic bones, and calcification of spinal ligaments. The radiological picture may mimic many other diseases, especially ankylosing spondylitis, diffuse idiopathic hyperostosis, and rare bone diseases, such as Albers-Schönberg disease. As clinical findings are often not characteristic, early diagnosis is based on the history of occupational exposure, examination of urinary fluoride excretion (over 8 mg F-/litre in 24 hours) and radiological signs. It is also useful to monitor the concentration of atmospheric fluoride.

Studies on fluoride excretion in human whole saliva and its relation to flow rate and plasma fluoride levels.

Five volunteers participated in two separate experiments where whole saliva was collected without stimulation or with stimulation by chewing on paraffin wax. The saliva was collected continuously for 120 min after ingestion of 1 mg fluoride as NaF. Blood was collected at intervals throughout the experiments. The results showed that the concentration of fluoride in whole saliva mirrored the fluoride concentration in plasma, but at a lower level. Variations in salivary flow rate (0.34 +/- 0.15 ml/min for unstimulated and 1.06 +/- 0.28 ml/min for stimulated) did not affect the salivary fluoride concentration. The amount of fluoride excreted into stimulated whole saliva was significantly correlated with the salivary flow rate, with a correlation coefficient of 0.98. The fraction of the ingested fluoride dose recovered in whole saliva within 2 h was 0.05 +/- 0.02 and 0.18 +/- 0.09% for the unstimulated and the stimulated whole saliva, respectively.

Influence of flow rate, pH and plasma fluoride concentratons on fluoride concentration in human parotid saliva

In two separate studies the influence of some physiological factors on salivary fluoride excretion was investigated. In the first study, parotid saliva, at two predetermined flow rates, and capillary blood were sampled after ingestion of 1 mg fluoride. In the second study, parotid saliva was collected at five different flow rates, starting 1 h after ingestion of 5 mg fluoride. Capillary blood was sampled throughout the experiment. The first study showed that parotid saliva and plasma fluoride concentrations were closely correlated ( r = 0.81). The mean parotid salivary and plasma fluoride concentration ratio (S/P ratio) ± SD ranged from 0.29 ± 0.11 to 0.65 ± 0.15. The fractions of the ingested fluoride dose excreted from one parotid gland were 0.08 and 0.18% at flow rates of 0.25 ± 0.02 and 0.49 ± 0.06 ml/min, respectively. The second study showed that at the mean basal plasma fluoride concentration of 0.65 ± 0.18 μmol/l the mean S/P ratio was 0.55 ± 0.24. At a plasma fluoride concentration ranging from 3.5 to 11.6 μmol/l the S/P ratio was 0.73 ± 0.15. Thus the S/P ratio was influenced by the plasma fluoride concentration, but not by variations in parotid salivary flow rate or pH.

I-653 Resists Degradation in Rats

The ability of rats pretreated with phenobarbital to metabolize a new volatile anesthetic, I-653, was compared with the metabolism of halothane, isoflurane, and methoxyflurane. Each anesthetic was administered for 2 hours at 1.6 MAC (inspired). Control rats were given phenobarbital but not exposed to an anesthetic. In rats pretreated with phenobarbital and exposed to I-653, fluoride ion concentrations in serum and excretion of fluoride ion and organic fluoride in the urine were almost indistinguishable from values measured in control rats. In contrast, rats pretreated with phenobarbital metabolized small but significant amounts of isoflurane. In rats pretreated with ethanol and exposed to I-653, the 24-hour excretion of urinary organic fluoride was nearly ten times greater than that observed in control rats. Marked increases in organic fluoride (as high as 1000 times control values) and/or fluoride ion were found in serum and/or urine after anesthesia of phenobarbital-pretreated rats with halothane or methoxyflurane. The relative stability of I-653 indicates that it may possess minimal toxic properties.

Urinary fluoride levels in pre-school children in relation to the use of fluoride toothpaste.

AbstractSamples of the first morning urine of 99 pre‐school children were collected on two successive days with children in the test group abstaining from the use of fluoride toothpaste on the day preceding the taking of the second sample. The fluoridexreatinine ratio of these children, an index of fluoride excretion, was lower in the second urine samples. If the results are representative of 24 hour urine samples it would appear that fluoride toothpaste may contribute significantly to the fluoride ingestion of pre‐school children.

Influence of type and level of dietary calcium on fluoride bioavailability in the rat

Two experiments were conducted with weanling rats fed a purified diet to determine the influence of dietary calcium (0.1, 0.2, 0.5, 1.0%) on fluoride bioavailability (2 or 10 ppm as sodium fluoride). The chemical form of calcium was the carbonate in experiment 1 and the gluconate in experiment 2. During each 6-week period the highest level of dietary calcium significantly reduced apparent fluoride absorption relative to controls (0.5% Ca), which was reflected in fluoride content of femur and most clearly in molar teeth, regardless of the solubility of calcium. When all levels of dietary calcium were considered, fecal fluoride excretion was found to be directly related to dietary calcium whereas urinary fluoride excretion was inversely related to calcium regardless of the solubility of calcium or the level of dietary fluoride. These effects, however, were markedly influenced by the fact that the amount of absorbed fluoride that was actually retained for incorporation into bones and teeth was directly related to dietary calcium level. Although high dietary calcium significantly depressed fluoride bioavailability during growth, it is equally clear that predictions about the magnitude of this relationship originating from gastric intubation studies have been greatly overstated.

Delayed fatal hyperkalemia in a patient with acute fluoride intoxication

A 19-year-old man presented with acute fluoride poisoning. Initially his serum electrolytes were normal, but two hours later he developed ECG evidence of hyperkalemia followed by refractory ventricular fibrillation, suggesting that hyperkalemia may be important in the cardiotoxicity of acute fluoride intoxication. Treatment of fluoride-induced hyperkalemia consists of removal of fluoride from the body by dialysis, binding fluoride with aluminum or calcium, or enhancing fluoride excretion by inducing a metabolic alkalosis. Direct treatment of the hyperkalemia with glucose, insulin, and bicarbonate is ineffective. Quinidine may be an effective therapy for the hyperkalemia and ventricular irritability, but is as yet untested in human beings.

Plasma fluoride concentration and urinary fluoride excretion in obese and non-obese patients following enflurane anesthesia.

Plasma fluoride concentrations and urinary fluoride excretions were measured following enflurane anesthesia (1.5%, 2 hours) in obese (8 cases) and non-obese (9 cases) patients. At the end of anesthesia, there was no significant difference in plasma fluoride concentrations between the two groups. In the several days following anesthesia, however, plasma fluoride concentrations in obese patients were higher than those in non-obese patients. Urinary fluoride excretions after anesthesia were greater in obese patients than those in non-obese patients, and the period of increased fluoride excretion was prolonged in obese patients. These results suggested that obese patients metabolized more enflurane than non-obese patients during the postanesthetic period. In obese patients, their excess fatty tissue may cause a greater and more prolonged elevation of blood enflurane concentrations after anesthesia.

Hepatic effects of repeated halothane anesthetics in the hypoxic rat model.

The hepatic effects of repeated anesthesia of phenobarbital-induced Fischer 344 rats with 1% halothane/14% oxygen were investigated, after anesthetics were administered at either 1-day or 5-day intervals. Urinary excretion of fluoride, a product of reductive halothane metabolism, was increased in the 24-h period following anesthesia, but was the same after the first, second, and third anesthetics. Rats killed 24 h after a single anesthetic all had centrilobular hepatocellular necrosis. All animals killed 24 h after the second or third anesthetic also had centrilobular necrosis, but, in most animals, this was no more extensive than that following a single anesthetic, regardless of whether the interval between anesthetics was one or five days.