Tomotaro Dote

Urinary biomarkers monitoring for experimental fluoride nephrotoxicity

Abstract An excess of sodium fluoride (135 mg F/kg body weight) was given in a single oral dose to male Wistar rats. Effects were investigated of fluoride-induced acute kidney intoxication on the time-dependent variations of urine volume. Also, of urinary fluoride ion (F−), α-glutathione-S-transferase (α-GST), N-acetyl-β-d-glucosaminidase (NAG), and creatinine (CR) concentrations. Fluoride administration strongly affects these urinary biochemical indices. Of the several biomarkers studied, α-GST is particularly useful as marker of S3 proximal tubule damage. We found that α-GST shows the strongest and more durable changes as a result of the large dose of F− given to the experimental animals. Our results suggest that the toxic effect of F− on the kidney may be more pronounced in the proximal tubule than the glomeruli region, and that the disorder of the proximal tubule is more serious in the S3 segment than S1 or S2 segment. α-GST proved to be a useful marker for the early detection and long-term observation of proximal renal tubular injury resulting from F− intoxication. The animal model should help to establish guidelines for the treatment of industrial workers suffering from acute renal failure resulting from accidental exposure to fluoride.

Successful treatments of lung injury and skin burn due to hydrofluoric acid exposure

Abstract Recent growth in the electronics and chemical industries has brought about a progressive increase in the use of hydrofluoric acid (HF), along with the concomitant risk of acute poisoning among HF workers. We report severe cases of inhalation exposure and skin injury which were successfully treated by administering a 5% calcium gluconate solution with a nebulizer and applying 2.5% calcium gluconate jelly, respectively. Case 1: A 52-year old worker used HF for surface treatment after welding stainless steel, and was hospitalized with rapid onset of severe dyspnea. On admission to the critical care medical center he had widespread wheezing and crackles in his lungs. Chest radiograph showed a fine diffuse veiling over both lower pulmonary fields. Severe hypocalcemia with high concentrations of F in serum and urine were disclosed. He was immediately given 5% calcium gluconate solution by intermittent positive-pressure breathing (IPPB), utilizing a neblizer. On the 21st hospital day, chest film and CT scan did not demonstrate any abnormality. He was discharged very much improved on the 22nd hospital day. Case 2: A 35-year old worker at an electronics factory was admitted to his local hospital with severe skin burn on his face and neck after exposure to 100% HF. Treatment began with immediate copious washing with water for 20 min. Calcium gluconate 2.5% gel (HF burn jelly) was applied to the area as a first-aid measure. Persistent high concentrations of serum and urinary F were disclosed for 2 weeks. After treatment with applications of HF burn jelly, he was confirmed as being completely recovered. The present cases and a review of published data suggest that an adequate method of emergency treatment for accidental HF poisoning is necessary.

Serum and urinary boron levels in rats after single administration of sodium tetraborate

Abstract The pharmacokinetics of boron was studied in rats by administering a 1 ml oral dose of sodium tetraborate solution to several groups of rats (n=20) at eleven different dose levels ranging from 0 to 0.4 mg/100 g body weight as boron. Twenty-four-hour urine samples were collected after boron administration. After 24 h the average urinary recovery rate for this element was 99.6 ± 7.9. The relationship between boron dose and excretion was linear (r=0.999) with a regression coefficient of 0.954. This result suggests that the oral bioavailability (F) of boron was complete. Another group of rats (n=10) was given a single oral injection of 2 ml of sodium tetraborate solution containing 0.4 mg of boron/100 g body wt. The serum decay of boron was followed and found to be monophasic. The data were interpreted according to a one-compartment open model. The appropriate pharmacokinetic parameters were estimated as follows: absorption half-life, t1/2a=0.608±0.432 h; elimination half-life, t1/2=4.64±1.19 h; volume of distribution, Vd=142.0±30.2 ml/100 g body wt.; total clearance, Ctot=0.359 ± 0.0285 ml/min per 100 g body wt. The maximum boron concentration in serum after administration (Cmax) was 2.13 ± 0.270 mg/l, and the time needed to reach this maximum concentration (Tmax) was 1.76 ± 0.887 h. Our results suggest that orally administered boric acid is rapidly and completely absorbed from the gastrointestinal tract into the blood stream. Boric acid in the intravascular space does not have a strong affinity to serum proteins, and rapidly diffuses to the extravascular space in proportion to blood flow without massive accumulation or binding in tissues. The main route of boron excretion from the body is via glomerular filtration. It may be inferred that there is partial tubular resorption at low plasma levels. The animal model is proposed as a useful tool to approach the problem of environmental or industrial exposure to boron or in cases of accidental acute boron intoxication.

An Overview of Boron, Lithium, and Strontium in Human Health and Profiles of These Elements in Urine of Japanese

The biological, medical and environmental roles of trace elements have attracted considerable attention over the years. In spite of their relevance in nutritional, occupational and toxicological aspects, there is still a lack of consistent and reliable measurement techniques and reliable information on reference values. In this review our understandings of the urinary profilings of boron, lithium and strontium are summarized and fundamental results obtained in our laboratory are discussed.Over the past decade we have successfully used inductively coupled plasma emission spectrometry for the determination of reference values for urinary concentrations of boron, lithium and strontium. Taking into account the short biological half-life of these elements and the fact that their major excretion route is via the kidney, urine was considered to be a suitable material for monitoring of exposure to these elements. We confirmed that urinary concentrations of boron, lithium and strontium follow a lognormal distribution. The geometric mean reference values and 95% confidence intervals were 798 μg/l (398–1599 μg/l) for boron, 23.5 μg/l (11.0–50.5 μg/l) for lithium and 143.9 μg/l (40.9–505.8 μg/l) for strontium. There were no discrepancies between our values and those previously reported. Our reference values and confidential intervals can be used as guidelines for the health screening of Japanese individuals to evaluate environmental or occupational exposure to these elements.

Toxicokinetics of intravenous fluoride in rats with renal damage caused by high-dose fluoride exposure

Abstract Fluoride (F) complexes are used in some fields of industry and medicine. F excretion mainly depends on kidney function. Urinary F concentration is measured to monitor the health of workers exposed to F. The toxicokinetics of F were studied by analyzing plasma concentration of F after intravenous injection of 2.86, 5.71 and 8.57 mg/kg into male Wistar rats. A dose–response relationship was recognized between these F doses and renal tissue injury. Blood samples were removed at 0, 10, 20, and 30 min, and after 1, 2, 3, 4, 5, and 6 h after injection. Plasma concentration-vs-time profiles were evaluated by a nonlinear least-squares method for fitting data to polyexponential equations and calculation of relevant pharmacokinetic parameters. Results indicated that a two–compartment model could describe the elimination of F from plasma. The β rate constant, total plasma clearance (Cl) and first-order rate constants (K21, Kel) decreased, and the half-time of the β-phase (t1/2β) was significantly prolonged with increasing dose. The kidney is the main target organ for F toxicity. Acute exposure to high doses of F damages renal tissue and causes renal dysfunction. The Cl of F is mainly dependent on renal F excretion. Since severe kidney damage markedly affected the toxicokinetics of F and decreased its elimination, other nephrotoxic indicators and measurement of plasma F concentration are necessary for monitoring high-dose F exposure.

Urine, serum and hair monitoring of hydrofluoric acid workers

SummaryTo define the relationship between fluoride (F) concentration in the serum, urine and hair of workers and the concentration of hydrofluoric acid (HF) in the work environment, pre- and postshift serum and urine samples of 142 HF exposed workers and 237 unexposed workers were examined. Hair specimens were also collected for the determination of F. To determine whether external contamination influences hair analysis, the control hair samples were kept in the work environment for one week. The pre-exposure levels in serum and urinary F in HF workers were higher (P<0.01) than the control values. This suggests that F excretion from the body continues for at least 12 hours. The postshift serum and urinary F concentrations of these workers were significantly higher (P<0.01) than the preshift concentrations. The levels of F in the hair of HF workers were also higher than in the control subjects. The concentrations of F in postshift serum and urine, and hair were in good correlation to each other. There was a linear relationship between mean serum and urinary F concentrations and HF concentration in the workplace. A mean F concentration of 82.3 μg/l in serum and 4 mg/l in urine with a lower fiducial limit (95%, P=0.05) of 57.9 μg/l in serum and 2 mg in urine were estimated to correspond to an atmospheric HF concentration of 3 ppm, which is the maximum allowable concentration recommended by Japan Association of Industrial Health and also the threshold limit value suggested by American Conference of Governmental Industrial Hygienists. F concentration in the hair increased after the hair samples were retained, however, it decreased to the reference value after washing treatment. The results support the speculation that F is excreted into the hair after long-term exposure to HF. From the results obtained, it was suggested that exposure to HF can be monitored by determining the serum, urinary and hair F concentrations.

Acute Lethal Toxicity, Hyperkalemia Associated with Renal Injury and Hepatic Damage after Intravenous Administration of Cadmium Nitrate in Rats

Acute Lethal Toxicity, Hyperkalemia Associated with Renal Injury and Hepatic Damage after Intravenous Administration of Cadmium Nitrate in Rats: Emi Dote, et al. Department of Hygiene and Public Health, Osaka Medical College—Cadmium nitrate Cd(NO3)2 (CdN) is commonly used in Ni‐Cd battery factories. The possibility of accidental exposure to CdN is great. CdN is very soluble in water compared to other Cd compounds. Therefore, acute toxicity would be expected to be quick due to rapid absorption after exposure. However, the mechanisms of CdN toxicity have not been fully elucidated. We investigated the acute lethal toxicity and harmful systemic effects of acute exposure to large doses of CdN. The lethal dose and dose‐response study of the liver and kidney were determined after intravenous administration of CdN in rats. The LD50 of CdN was determined to be 5.5 mg/ kg. Doses of 2.1, 4.2, 6.3 mg/kg were selected for the dose‐response study. Liver injury was induced at doses greater than 4.2 mg/kg. Severe hepatic injury occurred in the 6.3 mg/kg group, which would have been caused by acute exposure to the high concentration of Cd that exceeded the critical concentration in hepatic tissue. A remarkable decrease in urine volume in the 6.3 mg/ kg group indicated acute renal failure. A decrease in creatinine clearance suggested acute glomerular dysfunction at doses greater than 4.2 mg/kg. Increases in urinary N‐acetyl‐β‐D‐glucosaminidase/creatinine, β2‐microglobulin and glucose in the 6.3 mg/kg group indicated proximal tubular injury. Secretion of K ion was also severely affected by proximal tubular injury and severe decreases in urine volume, and an increase in serum K ion was identified at doses greater than 4.2 mg/kg. Thus severe hyperkalemia might be associated with the cardiac‐derived lethal toxicity of CdN.

Usefulness of the assessment of urinary enzyme leakage in monitoring acute fluoride nephrotoxicity

Abstract A single oral dose of sodium fluoride (NaF) in aqueous solution was given to male Wistar rats. Twenty-four-hour urine samples were collected and examined to evaluate fluoride-induced acute renal damage. The following parameters were measured in 24-h urine: urine volume and urinary excretion of fluoride, N-acetyl-β-d-glucosaminidase (NAG), α-glutathione-S-transferase (α-GST), and creatinine (CR). Fluoride exposure produced specific, dose-dependent changes of these parameters. Significant increases of fluoride and fluoride-induced polyuria were observed. NAG as specific marker of proximal convoluted tubule (PCT) function showed a significant increase when the lowest dose of fluoride was administered. At this minimal dose, α-GST, a specific marker for the S3 segment, did not show a significant increase but presented the strongest relationship (r = 0.83) to fluoride dose. No significant changes were measured for CR excretion, which showed a low correlation coefficient (r = 0.36) to administered fluoride. The specific differences in the increase pattern of these parameters show that the PCT is more susceptible to damage by low-dose fluoride than the S3 segment or the glomerulus. We concluded that both NAG and α-GST are useful for the diagnosis of fluoride-induced acute nephrotoxicity. Proper evaluation of these urinary indices may be of help to establish the site and extent of kidney injury in acute fluoride toxicity.

Strong Acute Toxicity, Severe Hepatic Damage, Renal Injury and Abnormal Serum Electrolytes after Intravenous Administration of Cadmium Fluoride in Rats

Strong Acute Toxicity, Severe Hepatic Damage, Renal Injury and Abnormal Serum Electrolytes after Intravenous Administration of Cadmium Fluoride in Rats: Kazuya Adachi, et al. Department of Hygiene and Public Health, Osaka Medical College—Cadmium fluoride (CdF) is commonly used as an insulator for ulta high speed mass telecommunications equipment, and there is a considerable risk that industrial workers will inhale CdF particles. Despite the possibility that acute exposure can cause harmful systemic effects, there are no studies to date that address the health consequences of acute CdF exposure. This study therefore aimed to determine the acute lethal dose of CdF and its effects on various target organs, including the liver and kidney. We also determined the effect of CdF on serum electrolytes and acid‐base balance. The effective lethal dose was determined and dose‐response study was conducted after intravenous administration of CdF in rats. The 24 h LD50 of CdF was determined to be 3.29 mg/kg. The dose‐response study used doses of 1.34, 2.67, 4.01 mg/kg CdF. Saline or sodium fluoride solution were used for controles. Severe hepatocellular injury was induced at doses greater than 2.67 mg/kg, as demonstrated by AST and ALT activities greater than 1,500 IU/l in rats injected with a dose of 4.01 mg/kg. Acute renal failure was induced at doses greater than 2.67 mg/kg. Decreased serum Ca, increased serum K and metabolic acidosis were induced at a dose of 4.01 mg/kg. Decreased serum Ca was caused by exposure to ionized F. CdF has the strongest lethal and hepatic toxicity among all Cd containing compounds.

Serum fluoride as an indicator of occupational hydrofluoric acid exposure.

SummaryTo define the relationship between ionic fluoride concentration in the serum of workers and the amount of hydrofluoric acid (HF) in the work environment, pre-and postshift serum and urine samples of 142 HF workers and 270 unexposed workers were examined. The maximum and minimum concentrations of HF in the air in each workshop varied from the mean by less than 30%. The pre-exposure levels of serum and urinary fluoride in HF workers were higher (P < 0.001) than the control values. This suggests that fluoride excretion from the body continues for at least 12 h. The postshift serum and urinary fluoride concentrations of these workers were significantly higher (P < 0.001) than the preshift concentrations. A good correlation (r = 0.64) was obtained between postshift serum fluoride and postshift urine fluoride. There was a linear relationship between mean serum fluoride concentration and HF concentration in the workshop. A mean fluoride concentration of 82.3 μg/l with a lower fiducial limit (95%, P = 0.05) of 57.9 μg/l was estimated to correspond to an atmospheric HF concentration of 3 ppm. This is the maximum allowable environmental concentration recommended by the Japanese Association of Industrial Health, and it is also the threshold limit value suggested by the American Conference of Governmental Industrial Hygienists. The results demonstrate that exposure to HF can be monitored by determining the serum fluoride concentration.