Human urinary and blood toxicokinetics of beryllium after accidental exposure.

PURPOSE: Beryllium is known to have adverse health effects and is classified as carcinogenic to humans. However, data on systemic beryllium exposure in humans are rare and especially human toxicokinetics are largely uncharted. As such, the first reported multi-annual course of blood and urine concentrations after a high exposure scenario provides important new insights. METHODS: For a medical follow-up biomonitoring samples were collected for 56 months from a male subject after an accidental and multi-faceted high exposure. Sampling started on day 2 post-exposure for urine and day 147 for blood. The samples were analyzed by inductively coupled mass spectrometry (ICP-MS) and plotted longitudinally as a function of time. Terminal half-lives were calculated assuming a first-order elimination process. MAIN FINDINGS: Both matrices showed highly increased initial concentrations (about 100-fold), despite the 147-day delay in blood sampling, and a marked decline over time. In urine, a two-phase excretion process was suspected based on the longitudinal data. Calculations gave terminal half-lives of 117.5 days and 666.5 days for phases 1 and 2, respectively. Blood kinetics called for a terminal half-life of 103.5 days. Elimination kinetics in blood and urine were comparable, simultaneously gathered samples showed an excellent correlation (R² = 0.985). PRINCIPAL CONCLUSIONS: The long-term follow-up after a high initial exposure to beryllium provides the first detailed insights into the elimination course of systemically available beryllium in humans. Conform kinetics of beryllium in urine and blood and the strong correlation between both parameters indicate high data validity and support the good representation of the current systemically available beryllium by urine and blood concentration in humans. The relatively long terminal half-lives in both matrices suggest a possible accumulation in humans in case of repeated exposures.

Serum and urinary concentrations of arsenic, beryllium, cadmium and lead after an aerobic training period of six months in aerobic athletes and sedentary people.

AIM: The aim of the present study was to evaluate the possible effect of a period of 6 months of aerobic physical training on serum and urinary concentrations of arsenic (As), beryllium (Be), cadmium (Cd) and lead (Pb), potentially toxic minerals. METHODS: Twenty-four well-trained, long distance runners (AG), were recruited at the start of their training period. They had been performing training regularly for the previous 2 years, recording an average volume of 120 km per week of rigorous aerobic exercise aimed at high-level competitions (1500 and 5000 m race modalities). Twenty-six untrained, sedentary participants constituted the control group (CG). All participants had been living in the same geographic area for at least 2 years before the start of the survey. Serum and urine samples were obtained from each participant at the beginning and at the end of the 6 months of the training program. The values of each mineral were determined by inductively coupled plasma mass spectrometry (ICP-MS). Additionally, the daily intake of each mineral was evaluated at both moments in time. RESULTS: The daily concentrations of trace elements in the diet were similar at the start and the end of the training period without differences between groups. In serum, significant differences between groups were observed in As, Cd and Pb (p < 0.05). Attending to time effects, a significant difference was obtained in Pb (p < 0.05). In urine, significant differences between groups were obtained in all minerals (p < 0.05). According to training period, significant differences were observed in As, Be and Pb (p < 0.05). Finally, the group x time interaction revealed significant differences in As and Be (p < 0.05). CONCLUSIONS: Aerobic training may constitute a possibly effective method for increasing the elimination of Cd and Pb potentially toxic minerals from the body, especially among highly trained individuals.

New insight in beryllium toxicity excluding exposure to beryllium-containing dust: accumulation patterns, target organs, and elimination.

There is much contradiction between different experimental studies on beryllium (Be) toxicity. The majority of studies focus on occupational pathologies, caused by the exposure to Be dust. However, Be pollution may affect wide population groups through other exposure routes. The discrepancies between experimental studies may be attributed to the lack of adequate Be toxicity model since conventional administration routes are hampered by high acidity and low solubility of Be compounds. This study was aimed to develop a novel way to implement Be toxicity avoiding side effects, related to high acidity or low solubility of Be salts. Intraperitoneal injection of Be-glycine composition (containing BeSO4, glycine, purified water, pH adjusted to 5.5 with NaOH) was tested in the dose range 238-7622 µmol Be kg-1 (body weight, b/w) in full-grown Wistar male rats. The model provided reliable uptake of Be from the peritoneum into general circulation for at least 48 h. LD50 was found to be 687 µmol Be kg-1 (b/w). The established LD50 value differed from previous data on gastrointestinal, intramuscular or intravenous administration of Be compounds. The liver was found to act as a primary elimination route for Be and related to the highest Be content in the animal. However, it had no signs of morphological damage, which was observed only in the testes (deterioration of germinal epithelium). At the same time, the lungs, stated as a primary target tissue for Be in the models of chronic beryllium disease, did not show strong Be accumulation nor morphological changes. Survived animals showed behavioral changes, including increased motor activity and aggressive reactions in some cases, and complete spasticity in other. The obtained data show the applicability of the established modeling protocol and testified for the independence of chronic beryllium disease on Be2+ ion toxicity per se.

Occupational exposure to beryllium in French industries.

Beryllium (Be) is a metal mainly used in the form of alloys, with copper (Cu) and aluminium (Al) in the metal industry. Be is an extremely toxic element which must be handled under strictly controlled conditions to avoid health hazards to workers. Exposure to Be can be responsible for Chronic Beryllium Disease, a pulmonary disease preceded by sensitization to the element, and for lung cancer. The goals of the current study were to investigate Be exposure in France, to determine the airborne Be occupational exposure levels, the associated impregnation of employees through their urinary Be levels and the factors that might affect them, and finally to study a possible relation between biomonitoring and airborne data. Seventy-five volunteer subjects were thus atmospherically and biologically monitored in five French companies involved in Cu or Al casting, Al smelting, CuBe machining or AlBe general mechanical engineering. Airborne exposure was quite low with only 2% of measurements above the current French Occupational Exposure Limit (2 µg/m3); the population potentially most exposed was foundry workers. Impregnation with Be was also low with only 10% of quantified urinary Be measurements above the current German BAR value (0.05 µg/L). Using a Bayesian statistical modelling approach, the mean subject-specific urinary excretion of Be was found to increase significantly with the mean subject-specific exposure to airborne Be. From this relationship, and based on the current French OEL-8 hr, a Biological Limit Value of 0.08 µg/L (= 0.06 µg/g creatinine) could be proposed.

[Distribution of rubidium, cesium, beryllium, strontium, and barium in blood and urine in general Chinese population].

OBJECTIVE: To investigate the distribution of rubidium (Rb), cesium (Cs), beryllium (Be), strontium (Sr), and barium (Ba) in blood and urine in general Chinese population. METHODS: A total of 18 120 subjects aged 6~60 years were enrolled from 24 regions in 8 provinces in Eastern, Central, and Western China from 2009 to 2010 based on the method of cluster random sampling. Questionnaire survey was conducted to collect the data on living environment and health status. Blood and urine samples were collected from these subjects, and the levels of Rb, Cs, Be, Sr, and Ba in these samples were determined by inductively coupled plasma mass spectrometry. The distribution of these elements in blood and urine in male or female subjects living in different regions was analyzed statistically. RESULTS: In the general Chinese population, the concentration of Be in the whole blood was below the detection limit (0.06 µg/L); the geometric mean (GM) of Ba in the whole blood was below the detection limit (0.45 µg/L), with the 95th percentile (P95)of 1.37 µg/L; the GMs (95% CI)of Rb, Cs, and Sr in the whole blood were 2 374(2 357~2 392) µg/L, 2.01 (1.98~2.05) µg/L, and 23.5 (23.3~23.7) µg/L, respectively; in males and females, the GMs (95%CI)of blood Rb, Cs, and Sr were 2 506 (2 478~2 533) µg/L and 2 248 (2 227~2 270) µg/L, 1.88 (1.83~1.94) µg/L and 2.16 (2.11~2.20) µg/L, and 23.4 (23.1~23.7) µg/L and 23.6 (23.3~23.9) µg/L, respectively(P<0.01, P>0.05, and P>0.05). In the general Chinese population, the GM of urine Be was below the detection limit (0.06 µg/L), while the GMs (95%CI)of urine Rb, Cs, Sr, and Ba were 854 (836~873) µg/L, 3.65 (3.56~3.74) µg/L, 39.5 (38.4~40.6) µg/L, and 1.10 (1.07~1.12) µg/L, respectively; in males and females, the GMs (95%CI)of urine Rb, Cs, Sr, and Ba were 876 (849~904) µg/L and 832 (807~858) µg/L, 3.83 (3.70~3.96) µg/L and 3.47 (3.35~3.60) µg/L, 42.5 (40.9~44.2) µg/L and 36.6 (35.1~38.0) µg/L, and 1.15 (1.12~1.19) µg/L and 1.04 (1.01~1.07) µg/L, respectively (all P< 0.01). Correlation analyses showed that there were weak correlations between blood Rb and urine Rb (r=0.197)and between blood Sr and urine Sr (r=0.180), but a good correlation between blood Cs and urine Cs (r=0.487). CONCLUSION: The levels of Rb, Cs, Be, Sr, and Ba in the general Chinese population are similar to those reported in other countries, and there is a significant difference in the concentration of each element among the populations living in different regions, as well as significant differences in blood Rb, urine Rb, urine Cs, urine Sr, and urine Ba between males and females.

Validation of a standardised method for determining beryllium in human urine at nanogram level.

The potential toxicity of beryllium at low levels of exposure means that a biological and/or air monitoring strategy may be required to monitor the exposure of subjects. The main objective of the work presented in this manuscript was to develop and validate a sensitive and reproducible method for determining levels of beryllium in human urine and to establish reference values in workers and in non-occupationally exposed people. A chelate of beryllium acetylacetonate formed from beryllium(II) in human urine was pre-concentrated on a SPE C18 cartridge and eluted with methanol. After drying the eluate, the residue was solubilised in nitric acid and analysed by atomic absorption spectrometry and/or inductively coupled plasma mass spectrometry. The proposed method is 4 to 100 times more sensitive than other methods currently in routine use. The new method was validated with the concordance correlation coefficient test for beryllium concentrations ranging from 10 to 100 ng/L. Creatinine concentration, urine pH, interfering compounds and freeze-thaw cycles were found to have only slight effects on the performance of the method (less than 6%). The effectiveness of the two analytical techniques was compared statistically with each other and to direct analysis techniques. Even with a detection limit of 0.6 ng/L (obtained with inductively coupled plasma mass spectrometry), the method is not sensitive enough to detect levels in non-occupationally exposed persons. The method performance does however appear to be suitable for monitoring worker exposure in some industrial settings and it could therefore be of use in biological monitoring strategies.

Beryllium in urine by ICP-MS: a comparison of low level exposed workers and unexposed persons.

PURPOSE: To develop a sensitive and reproducible method for urinary beryllium and to use this method to establish levels in workers at an aluminium smelter and in unexposed persons. METHODS: A method was developed for urinary beryllium using a Thermo ICP-MS Series 1, which was used to determine beryllium concentrations in urine from 62 people with no known occupational exposure to beryllium and 167 workers with potential exposure to beryllium at an aluminium smelter, where beryllium exists as an impurity in the bauxite ore. RESULTS: The analytical method has a detection limit (based on three times the background equivalent concentration of the blank) for beryllium in urine of 6 ng/L. The mean and 90th percentiles of urinary beryllium for workers were 19.5 and 42.0 ng/L and compared with 11.6 and 20.0 ng/L in people not occupationally exposed to beryllium. Statistical analysis using mixed effects models showed that workers had 47% (in 135 paired samples) higher levels of urinary beryllium at the end of the working week compared to the start of week and that the workers who smoked also had significantly higher levels of urinary beryllium compared to those that did not smoke. There was also a statistically significant difference between workers and controls in urinary beryllium concentrations not corrected for creatinine. CONCLUSIONS: A sensitive and reliable analytical method was developed for urinary beryllium by ICP-MS. The workers in this study were exposed to beryllium at very low levels.

Determination of urinary beryllium, arsenic, and selenium in steel production workers.

Some of the most pernicious dangers of pollution arise from the presence of traces of toxic elements in the environment. In this work, we report on the determination of beryllium, arsenic, and selenium in the urine of steel production and steel quality control (QC) workers, in comparison to healthy control subjects. The urine samples were digested by a microwave system. Graphite furnace and hydride atomic absorption was used for the quantitative measurements of Be and As and Se, respectively. A quality control method for these procedures was established with concurrent analysis of Standard Trace Metals 7879 Level II and NIST SRM 2670 (Toxic Elements in Freeze Dried Urine). The results show that the urinary levels of these elements in steel production (As, 38.1 +/- 28.7 microg/L; Be, 1.58 +/- 0.46 microg/L, and Se, 69.2 +/- 28.8 +/- g/L) and in quality control workers (As, 23.9 +/- 18.1 microg/L; Be, 1.58 +/- 0.46 microg/L, and Se, 54.8 +/- 25.1 microg/L) are significantly higher than in the controls (As, 10.3 +/- 8.7 microg/L; Be, 0.83 +/- 0.46 microg/L; and Se, 32.3 +/- 13.5 microg/L). The possible connection of these elements with the etiology of disease and the possible role of selenium as a protective agent against the oncogenic and teratogenic action of other substances is discussed. We suggest the need for improvement of environmental conditions in the workplace through better ventilation and industrial hygiene practices.

Urinary beryllium--a suitable tool for assessing occupational and environmental beryllium exposure?

OBJECTIVES: The reasons for the slow progress and lack of new knowledge in the biological monitoring of beryllium (Be) are to be found in the presumed small number of working activities involving exposure to the metal, and the lack of adequate analytical methods. The reference values for urinary Be reported earlier in the literature appear to be too high, due to the poor specificity and sensitivity of the adopted methods. The aim of this study was to correlate Be air concentrations and Be urinary levels to ascertain whether the biological indicator was suitable for assessing occupational exposure to the metal. METHODS: To investigate the relationship between the Be concentrations in air and those excreted in urine, we examined 65 metallurgical workers exposed to very low levels of the metal, and 30 control subjects. The exposed workers were employed in two electric steel plants and two copper alloy foundries. The alloys were produced in electric furnaces, starting with scrap containing Be as an impurity. The Be concentrations in the air were monitored by area samplers and the levels of Be in the urine of the workers were determined in samples taken at the end of the shift. Both determinations were carried out by ICP-MS. RESULTS: The median airborne Be concentrations in the copper alloy plants were 0.27 microgram/m3 in the furnace area and 0.31 microgram/m3 in the casting area. Median values of 0.03 to 0.12 microgram/m3 were determined in the steel plants, the relatively wide range probably due to differing amounts of Be in the scrap. Regression analysis was performed on the median values from four work areas and the corresponding urinary samples. A significant correlation was found for the relationship between external and internal exposure. The urinary Be levels were in the range between 0.12 and 0.15 microgram/l with observation of the recommended TLV-TWA for inhalable dust of 0.2 microgram/m3 (0.2 microgram/l at the upper 95th percentile). CONCLUSIONS: Sufficient data are not currently available to be able to propose a BEI for urinary Be. Our results show that new investigations are necessary to improve the evaluation of dose indicators and the relationship between external and internal exposure to Be.

Determination of beryllium and selenium in human urine and of selenium in human serum by graphite-furnace atomic absorption spectrophotometry.

For human urine beryllium (Be), each sample (500 microl) was diluted (1+1) with Nash reagent (containing 0.2% (v/v) acetylacetone and 2.0 M ammonium acetate buffer at pH 6.0) and then a 20-microl volume of Triton X-100 (0.4%, v/v) aqueous solution was added. An aliquot (10 microl) of the diluted urine mixture was introduced into a graphite cuvette and was atomized according to a temperature program. The method detection limit (MDL, 3sigma) for Be was 0.37 microg/l in the undiluted urine sample and the calibration graph was linear up to 65.0 microg/l. Calibration graphs were prepared by the standard addition method. Accuracies of 98.6-102% were obtained when testing standard reference material (SRM 2670) freeze dried human urine samples. Precision (relative standard deviation, RSD) for urine Be was < or = 2.3% (withinrun, n = 5) and was < or = 3.0% (between-run, n = 3). For human urine and serum selenium (Se), samples (100 microl) were diluted with HNO3 (0.2%, v/v) to make a (1+1) dilution for urine analysis or a (1+4) dilution for serum analysis. An additional aliquot (10 microl) of Triton X-100 (0.1%, v/v) was added to each 200 microl of (1+1) diluted urine (or 20 microl of the Triton X-100 was added to each 500 microl of (1+4) diluted serum) sample. After the diluted sample mixture (10 microl) was introduced into a graphite cuvette, the corresponding chemical modifier (10 microl, containing Ni2+ + Pd + NH4NO3 in HNO3 (0.2%, v/v)) was added to it and the mixture was atomized. The MDL (3sigma) for Se in urine and in serum was 4.4 and 21.4 microg/l in undiluted sample, respectively, and the calibration graphs were linear up to 150 and 400 microg/l. Accuracies of urine Se were 98.9 - 99.4% by testing SRM 2670 (NIST) urine standards with RSD (between-run, n = 3) within 2.9%; and that of serum Se was 97.2% when testing a certified second-generation human serum (No. 29, #664) with RSD (between-run, n = 3) of 1.4%. The proposed method can be applied easily, directly, and accurately to the measurement of Be and Se in real samples (including six urine Se and four serum Se from patients of Blackfoot Disease in Taiwan).

Effects of meso-2,3-dimercaptosuccinic acid or 2,3-dimercaptopropane 1-sulfonate on beryllium-induced biochemical alterations and metal concentration in male rats.

The effects of two chelating agents, meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane 1-sulfonate (DMPS) on the mobilization, distribution, hepatic and hematopoietic toxicity of beryllium were compared in male rats exposed to beryllium. Animals were exposed to beryllium nitrate (0.5 mg/kg, orally, daily 5 days/week) for 21 days. Twenty-four hours after the last dose they were injected with a chelating agent (DMSA or DMPS) (25 or 50 mg/kg, twice daily for 5 days). The administration of DMSA and DMPS at a dose of 50 mg/kg marginally elevated the fecal excretion of beryllium. DMPS was effective in depleting beryllium from the liver, spleen and kidneys. However, DMPS (50 mg/kg) results in the redistribution of beryllium to blood. Beryllium-induced inhibition of hepatic alkaline phosphatase and hepatic adenosine triphosphatase (ATPase) were restored considerably with the chelating agents. Also, hepatic and renal histopathological lesions were less marked in rats treated with DMPS (50 mg/kg) compared with those treated with beryllium per se and DMSA. These effects were more prominent at the 50-mg/kg dose of chelating agents than at 25 mg/kg. These results suggest that treatment with DMPS has some beneficial effects in experimental beryllium intoxication.

Beryllium metal solubility in the lung, comparison of metal and hot-pressed forms by in vivo and in vitro dissolution bioassays.

The solubility of two industrial forms of beryllium, i.e. particles of metal powder and particles of hot-pressed beryllium, was investigated using in vivo and in vitro models. In the in vivo model, baboons and rats were used and were injected via the trachea with amounts of beryllium equivalent to 100,500 and 1000 fold the maximum permissible concentration (MPC) recommended by the US Occupational Safety and Health Administration. In vivo experiments showed that in both species the daily beryllium solubility rates were about 5 X 10(-6) for metal particles and that in rats the daily beryllium solubility rate was about 5 X 10(-5) for the hot-pressed particles. During the 10 months of the experiment with baboons, urinary excretion of beryllium was proportional to the amount administered. With regard to results for the in vitro models, the outcome of the acellular dissolution test using a serum simulant was not consistent with the in vivo results, though a cellular model using cultured macrophages showed the same trends in the dissolution rates for the two forms of beryllium as those observed in vivo. This result suggest that a cellular rather than an acellular dissolution model would be better a predicting solubility of beryllium compounds in the lungs.

Toxicokinetic and toxicodynamic studies of beryllium.

The question of dose-effect relations of berylliosis was examined by measuring the Be-concentration in blood and urine, as well as the immunological behaviour of T-lymphocytes for a group of occupationally exposed men (smaller than 8 ng Be/m3, 4-6 h daily) and a non-exposed control group. Normal values 1.0 +/- 0.4 ng Be/g(n=10) in blood and 0.9 +/- 0.5 ng Be/g(n=10) in urine were found by an optimized flameless atomic absorption spectrometry method. The corresponding values for the exposed group (n=8) showed a mean increase of a factor of 4. The preferential enrichment of Be in the prealbumin and in the nu-globulin fractions was determined by a preparative isotachophoretic column with physiological pH conditions, especially developed for this application. The Be-specific stimulation of the T-lymphocytes of the exposed group was increased significantly. In blood and urine samples of exposed (2-40 mg Be/m3 as Be(NO3)2) Wistar-rats and guinea pigs Be values up to 36 ng Be/g in serum and up to 300 ng Be/g in urine were determined. After Be exposure, guinea pig serum showed a significant increase in the nu-globulins after the isotachophoretical separation of the serum proteins, which could not be correlated with increased Be-levels in this fraction. 70% of the total Be(10-100 ng/g serum) were detected in the prealbumin, only about 1% in the nu-globulin fraction. The same results were found in serum samples with in vitro addition of Be. The lymphocyte transformation rates for the exposed animals were increased. Skin tests were found to be positive in 70% for exposed rats and in 50-70% for guinea pigs.