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Molybdenum is an essential trace element for mammalian, plant, and other animal systems. The Institute of Medicine (IOM) has established an Estimated Average Requirement (EAR) to assure sufficient molybdenum intakes for human populations; however excessive exposures can cause toxicity. As a result, several agencies have established exposure guidance values to protect against molybdenum toxicity, including a Reference Dose (RfD), Tolerable Daily Intake (TDI) and a Tolerable Upper Intake Level (UL). Biomonitoring for molybdenum in blood or urine in the general population is being conducted by the Canadian Health Measures Survey (CHMS) and the U.S. National Health and Nutrition Examination Survey (NHANES). Using pharmacokinetic data from controlled human dosing studies, Biomonitoring Equivalents (BEs) were calculated for molybdenum in plasma, whole blood, and urine associated with exposure guidance values set to protect against both nutritional deficits and toxicity. The BEEAR values in plasma, whole blood and urine are 0.5, 0.45 and 22 μg/L, respectively. The BEs associated with toxicity range from 0.9 to 31 μg/L in plasma, 0.8-28 μg/L in whole blood and 200-7500 μg/L in urine. These values can be used to interpret molybdenum biomonitoring data from a nutritional and toxicity perspective., (Copyright © 2016. Published by Elsevier Inc.)

Background: Despite the theoretical advantages of ceramic-on-metal (CoM) bearings observed in laboratory settings, limited clinical data are available to support in vitro results. Our present study prospectively investigated the clinical results, serum metal ion levels, inflammatory factor levels, and liver-kidney function in a cohort of patients who received total hip arthroplasty (THA) with CoM bearings., Methods: The cohort comprised 82 THAs in 71 patients (41 men and 30 women), with a mean age of 54 (range 22-77) years. The mean follow-up was four years. All patients completed pre- and postoperative clinical assessment using the Harris Hip Score, Short Form-12, Western Ontario and McMaster Universities Osteoarthritis Index, and radiographic analysis. The serum metal ion levels of cobalt, chromium, molybdenum, and titanium were measured using high-resolution inductively coupled plasma mass spectrometry, and were compared with normal reference values. Inflammatory factors including C-reactive protein, erythrocyte sedimentation, and interleukin-6 levels, and liver-kidney function including alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatinine, and blood urea nitrogen, were measured in our hospital clinical key laboratory., Results: At the end of the follow-up period, all clinical assessments showed a statistically significant improvement. Although the inflammatory factor levels and liver-kidney function were within normal ranges, the serum levels of metal ion were significantly elevated compared with normal values: cobalt, 2.8 μg/L; chromium, 2.2 μg/L; molybdenum, 0.9 μg/L; and titanium, 2.1 μg/L. Spearman's correlation analysis showed an association between cobalt, chromium, and titanium metal ion levels and BMI values., Conclusions: Our study demonstrated that the use of a CoM THA was clinically effective and that metal ion levels were significantly elevated at midterm follow-up. Whether the elevated metal ion levels may reduce adverse reactions is unknown, and long-term follow-up is needed.

This study investigated the subchronic toxicity of molybdenum (Mo) in Sprague-Dawley rats given sodium molybdate dihydrate in the diet for 90days at dose levels of 0, 5, 17 or 60mgMo/kgbw/day. The study complied with OECD Test Guideline (TG) 408, with additional examination of estrus cycles and sperm count, motility, and morphology from OECD TG 416. The overall no-observed-adverse-effect level was 17mgMo/kgbw/day, based on effects on body weight, body weight gain, food conversion efficiency and renal histopathology (females only) at 60mgMo/kgbw/day. No treatment-related adverse effects on reproductive organ weights or histopathology, estrus cycles or sperm parameters were observed at any dose level. No adverse effects were observed in the high dose animals after the 60-day recovery period, with the exception that male rats did not fully recover from reduced body weight. Serum blood, liver and kidney samples were analyzed for molybdenum, copper, zinc, manganese, iron, cobalt and selenium; high levels of molybdenum and copper were found in the serum, blood, liver and kidneys of rats treated with 60mgMo/kgbw/day. In conclusion, the LOAEL and NOAEL for molybdenum were determined to be 60 and 17mgMo/kgbw/day, respectively., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

A simple, ultrasensitive, nonextractive spectrophotometric method has been developed for the assay of Mo(VI), which involves Mo-catalyzed oxidation of 4-amino-5-hydroxynaphthalene-2,7-disulfonic acid monosodium salt (AHNDSA) by H(2)O(2) in acetic acid/sodium acetate buffer yielding an intense pink colored product with λ(max) of 540 nm. Beer's law is obeyed in the range of 10-240 ng/ml with molar absorptivity of 3.0137×10(5)L mol(-1)cm(-1). The LOD and LOQ were found to be 0.7696 and 2.565 ng/ml, respectively. The applicability of the method toward water and biological samples was tested and statistically compared with a reference method., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The objectives of this study were to determine physiologic adaptations that occur when humans are exposed to a wide range of molybdenum intake levels and to identify the pathways that are influenced by dietary intake. Four males consumed each of 5 daily molybdenum intakes of 22, 72, 121, 467, and 1490 microg/d (0.23, 0.75, 1.3, 4.9, and 15.5 micromol/d) for 24 d each. During each treatment period, oral and intravenous doses of (100)Mo and (97)Mo were administered. Serial plasma, urine, and fecal samples were analyzed for labeled and unlabeled molybdenum. Compartmental modeling was used to determine rates of distribution and elimination at each dietary intake level. Three pathways were sensitive to daily molybdenum intake. With increasing intake, absorption and urinary molybdenum excretion increased, whereas the fraction deposited in tissues decreased. Kinetic analysis suggested a daily intake of 115-120 microg/d (1.20-1.25 micromol/d) would maintain initial plasma molybdenum levels at their prestudy values and that their prestudy dietary intake was well above the Recommended Dietary Allowance of 45 microg/d. The physiological adaptations to changing intake that the model demonstrated may help prevent molybdenum deficiency and toxicity.

Copper (Cu) accumulating in a form bound to metallothionein (MT) in the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease, was removed with ammonium tetrathiomolybdate (TTM), and the fate of the Cu complexed with TTM and mobilized from the liver was determined. TTM was injected intravenously as a single dose of 2, 10 or 50 mg TTM/kg body weight into LEC and Wistar (normal Cu metabolism) rats, and then the concentrations of Cu and molybdenum (Mo) in the bile and plasma were monitored with time after the injection. In Wistar rats, most of the Mo was excreted into the urine, only a small quantity being excreted into the bile, while Cu excreted into the urine decreased. However, in LEC rats, Cu and Mo were excreted into the bile and blood, and the bile is recognized for the first time as the major route of excretion. The Cu excreted into both the bile and plasma was accompanied by an equimolar amount of Mo. The relative ratio of the amounts of Cu excreted into the bile and plasma was 40/60 for the low and high dose groups, and 70/30 for the medium dose group. The systemic dispositions of the Cu mobilized from the liver and the Mo complexed with the Cu were also determined for the kidneys, spleen and brain together with their urinal excretion. Although Mo in the three organs and Cu in the kidneys and spleen were increased or showed a tendency to increase, Cu in the brain was not increased at all doses of TTM.

Tetrathiomolybdate (TTM) can be used as a specific chelator to remove copper (Cu) accumulating in the form bound to metallothionein (MT) in the livers of Wilson disease patients and Long-Evans rats with a cinnamon-like coat color (LEC rats). However, an adverse effect, hepatotoxicity, was observed occasionally on its clinical application. The mechanism underlying the adverse effect of TTM has been studied in comparison with dithiomolybdate (DTM), and a safer and more effective therapy by TTM was proposed based on the mechanism. The activity of glutamic-pyruvic transaminase (GPT) in serum was shown to increase significantly on the treatment of Wistar rats with sulfide produced through hydrolytic degradation of TTM and DTM, the latter being more easily degraded. The hydrolytic degradation of TTM was enhanced under acidic conditions. Cu in Cu-containing enzymes such as Cu,Zn-superoxide dismutase (SOD) in liver and ceruloplasmin (Cp) in plasma was decreased by excessive thiomolybdates, the Cu being found in the plasma in the form of a Cu/thiomolybdate/albumin complex. The decreased amounts of Cu in SOD and Cp were explained by the sequestration of Cu from their chaperones by thiomolybdates rather than the direct removal of Cu from the enzymes. Although both TTM and DTM remove Cu from MT, DTM is not appropriate as a therapeutic agent for Wilson disease due to its easy hydrolysis and production of sulfide.

The uptake of tetrathiomolybdate (TTM) by the liver and the removal of copper (Cu) accumulating in the liver in a form bound to metallothionein (MT) by TTM were studied in Long-Evans cinnamon (LEC) rats, an animal model of Wilson disease, in order to develop better treatments for the disease and Cu toxicity. Although molybdenum (Mo) was incorporated in a dose-dependent manner into the livers of both LEC and Long-Evans agouti (LEA) rats, the original strain of LEC rats used as a reference animal, the uptake into the liver of LEC rats was 13 times higher than that in LEA rats. The concentration of Mo in the soluble fraction plateaued and it was distributed more in the insoluble fraction with a higher dose in LEC rats. The concentration of Cu in the whole livers of LEC rats was decreased by TTM in a dose-dependent manner only at lower doses. However, the concentration of Cu in the soluble fraction continued to decrease with the dose of TTM. The results can be explained in terms of complex formation. Namely, TTM forms a complex with Cu, tentatively referred to a Cu/TTM complex, that can be effluxed into the bloodstream, and then binds selectively to albumin when the dose of TTM is low. On the other hand, TTM forms an insoluble complex, named as a Cu/TTM polymer that is precipitated in the liver when the dose is high. The results further indicate that TTM taken up by a cell is immobilized in the cell through the dose-dependent formation of a complex containing Cu, Mo and sulfur (S), which causes further uptake of TTM. TTM injected into rats or incubated in vitro with serum does not remove Cu from ceruloplasmin. TTM is, thus, suggested to target a cell accumulating excess Cu as Cu-MT, and to remove Cu selectively without interacting with Cu in Cu-enzymes. The results indicate that TTM is taken up by the liver depending on the amount of Cu accumulating in the form of MT, and then Cu is effluxed together with Mo in the form of Cu/TTM complex into the bloodstream.

Examination of direct and (Cu)-difference spectra of i) the aqueous supernatants of in vitro cultures of bovine rumen contents incubated with MoO42- and potential sources of S2- and ii) samples drawn directly from the rumen of animals receiving high Mo diets yielded evidence of the presence of thiomolybdates. Only MoS42- was detected in the soluble phase of in vitro cultures. Although intense and variable background absorbance precluded full characterization of thiomolybdate species in samples drawn directly from the rumen, both spectral data and the biochemical and clinical responses of animals given high Mo diets were consistent with the conclusion that MoS42- rather than MoOS32- was the predominant thiomolybdate species present in the aqueous phase. Addition of Ca2+ either to rumen cultures before incubation or as a supplement to diets high in MoO42- content inhibited the appearance of MoS42- in the aqueous phase. Evidence of the sequestration of MoS42- and MoOS32- by particulate or microbial fractions of rumen contents is considered in relation to the inhibitory action of Mo upon Cu absorption by ruminants.

An initial experiment showed that [99Mo]di- and trithiomolybdates could be detected in bovine plasma after the introduction of [99Mo]molybdate into the rumen. It was felt that this justified the use of [99Mo]trithiomolybdate for the subsequent studies made of plasma thiomolybdate metabolism in vivo in cattle. Rapid intravenous injection of [99Mo]trithiomolybdate into cattle showed that doses of 50 mg Mo were subject to extensive hydrolysis over the first few minutes postinjection, but at lower dose rates this was reduced so that tracer doses (less than 1.5 mg Mo) were relatively stable. The plasma metabolism was unaffected by copper status within the limits of the experiments (that is, liver copper levels down to 9 mg/kg d.m.) The disappearance of [99Mo] and [35S]trithiomolybdate (1 mg Mo) from plasma was delayed for up to 10 hr by the immediate preinjection of copper, although no chemical modification of the thiomolybdate appeared to occur.

The absorption of labelled molybdenum compounds was studied in pairs of sheep exchanging digesta via re-entrant duodenal cannulae. Tri- and tetrathiomolybdate 99Mo were rapidly absorbed from the rumen to circulate in plasma in a protein-bound and in a TCA-insoluble form. The compounds were also absorbed from the small intestine although some breakdown was evident. Initially, molybdate was poorly absorbed from the rumen but after several hours the concentration of protein-bound, TCA-insoluble 99Mo increased in plasma. This provides evidence of rumen thiomolybdate synthesis. The results indicate that thiomolybdates are absorbed directly from the rumen and despite the sensitivity of the compounds to acid, some absorption from the small intestine occurs after passage through the abomasum. Rumen absorption could be a contributory factor to ruminant sensitivity to the effects of Mo compounds.

As one of a series of studies on the influence of S substitution of MoO4(2-) on the action of Mo as an antagonist of Cu, the effects of MoO2S2(2-) and MoOS3(2-) on the metabolism of Cu by rats have been investigated. Administration of either oxythiomolybdate increased both plasma Cu concentration and the retention of Cu by the albumin fraction of plasma. In contrast to the effects of MoS4(2-), described previously, neither oxythiomolybdate inhibited 64Cu absorption from the digestive tract or induced biochemical or clinical signs of Cu deficiency. Evidence is discussed suggesting that the potency of the thio- and oxythiomolybdates as inhibitors of Cu utilization is directly proportional to the degree of thio substitution within the series series MoO4- chi S chi 2-.

Several investigators have reported serum molybdenum determinations in healthy humans. However, their results diverge quite widely. We determined the element by neutron activation analysis in 30 individuals. We found a mean value of 0.58 ng/ml, a standard deviation of 0.21 ng/ml and a range of 0.28--1.17 ng/ml.

The effect on Cu metabolism of two organic Mo compounds, cysteine-Mo (CM) and cysteine-Mo-S (CMS), and of an inorganic compound, tetrathiomolybdate (TTM), was investigated in sheep. Intravenous administration of CMS or TTM increased total plasma Cu concentrations and promoted the appearance of trichloroacetic acid (TCA)-insoluble Cu in plasma. Plasma Mo was increased by both compounds. Column chromatography of plasma showed that CMS caused the accumulation of TCA-insoluble Cu in high-MW fractions, whereas TTM increased the Cu content of low-MW fractions, mainly albumin. CMS and TTM increased the concentration of Cu and Mo in kidney. In liver, Mo concentrations were elevated by both CMS and TTM, and Cu concentrations were reduced by TTM when it was given at a low dose rate. The subcellular distribution of Cu and Mo in liver and kidney was investigated. The findings are discussed in relation to the proposal that Mo-containing, organic compounds are intermediaries in the interaction between Cu, Mo, and S in ruminants.

Spectral studies showed that copper and trithiomolybdate participated in a three-way interaction with bovine and canine serum albumin. The interaction with the proteins was affected by increased pH and ionic strength. Kinetic studies of binding equilibria indicated that [35S] trithiomolybdate bound to both albumins at a single site. The affinity of the site, but not the capacity of the protein, was increased by copper. It was concluded that the site was distinct from the N-terminal copper (and nickel) binding site, which is present on BSA but absent from CSA. Whether or not the N-terminal site has a role in copper transport is discussed. Reversible thiomolybdate-copper-protein interactions of this type may play a fundamental role in the pathogenesis of Mo-induced syndromes, since as the normal binding patterns are perturbed the interprotein equilibria are altered and the copper distribution patterns are modified.

We determined the serum molybdenum concentration by neutron activation analysis in apparently healthy subjects and in patients with diseases of the liver and biliary system. The level was found to be markedly elevated in the initial phase of acute viral hepatitis (mean +/- S.D. 3.10 +/- 1.46 ng/ml vs. 0.55 +/- 0.21 in controls) and to return to normal during convalescence, in parallel with the liver function tests. The most significant correlations were found between the serum molybdenum concentration and the serum levels of GOT ( r = 0.710, p less than 0.001) and GPT (r = 0.683, p less than 0.001). Besides, the serum molybdenum level (mean +/- S.D.) was observed to be definitely increased in patients with HBsAg-positive chronic active hepatitis (0.97 +/- 0.49 ng/ml), HBsAg-positive liver cirrhosis (1.01 +/- 0.50), alcoholic liver disease (1.32 +/- 0.56), liver metastases (1.40 +/-0.39), gallstones (1.28 +/- 0.38), tumors of the gallbladder or extrahepatic bile ducts (1.64 +/- 0.44), and carcinoma of the head of the pancreas (1.61 +/- 0.91). Finally, the serum molybdenum level was found to be raised in two patients with primary biliary cirrhosis and in two out of four patients with drug-induced liver injury. The etiologic mechanism and the clinical importance of the observed abnormality remain to be established. Our study enlarges the existing information concerning the disorders of trace element metabolism in liver diseases.

After incubating plasma of Mo-supplemented rats (Mo-plasma) with 64Cu only part of it could be removed by dialysis against EDTA or histidine or by treatment with dithiocarbamate; this nondialyzable Cu was shown to be bound to albumin. The maximal amount of 64Cu bound this way equaled the Mo-induced increase in total plasma Cu. After addition of stable Cu, dialysis of Mo-plasma against a histidine solution showed that no extra Cu became tightly bound, suggesting that the 64Cu binding was due to an exchange between added 64Cu and stable Cu already present. Incubating Mo-plasma with Hg compounds prevented 64Cu binding and released stable Cu, indicating that Cu in Mo-plasma was sulfhydryl bound. Part of the Mo in Mo-plasma was freely dialyzable. The remaining part was shown to be SH bound as well. The estimated atomic ratio of SH-bound Cu and Mo was unity. Molybdenum increased the number of SH groups in plasma, and for each Cu atom at least one SH group was calculated to be present.

The effects of molybdenum ingestion on copper metabolism were investigated in bile duct-cannulated ponies fed diets containing 1.01, 27.4 and 107.3 ppm molybdenum. Copper metabolism was assessed by examination of 64Cu and stable copper excretion in feces, bile and urine. The addition of molybdenum to the diet decreased copper absorption and retention as a consequence of increased excretion of dietary copper in feces and increased excretion of absorbed copper in bile. Only 5% or less of the absorbed copper was excreted in urine regardless of dietary treatment. Biliary molybdenum excretion was only 0.86 mg per 100 kg of body weight per day even when ponies were fed the highest level of molybdenum. However, increased molybdenum ingestion produced elevations in protein bound copper in bile. Molybdenum was absorbed by ponies but urinary excretion was effective in eliminating most of the element from the body.