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Associations between molybdenum exposure and ultrasound measures of fetal growth parameters: A pilot study

Previous studies have suggested the association of molybdenum (Mo) exposure with some adverse outcomes. However, limited epidemiological studies have been performed to explore the association between maternal Mo exposure level and fetal growth. This study recruited 220 pregnant women during their second trimester. The mother's urinary Mo concentration was measured by inductively coupled plasma mass spectrometry (ICP-MS). The fetal biometric parameters, including head circumference (HC), biparietal diameter (BPD), femur diaphysis length (FL), and abdominal circumference (AC) were assessed by prenatal ultrasound. Estimated fetal weight (EFW) was evaluated using the formula of Hadlock. Multivariable linear regression models were applied to estimate the relationships between Mo level and fetal biometric parameters, and potential confounders were adjusted. A one-unit increment in natural-logarithm transformed urinary Mo level was significantly associated with reductions in fetal AC of -0.34 cm (95%CI: -0.63, -0.04), and was negatively related to EFW (β = -18.2, 95%CI: -40.5, 4.2). Furthermore, when participants were stratified by copper (Cu) level, the results showed that the magnitude of negative association between Mo and AC (β = -0.55, 95%CI: -1.13, 0.04) was greater in pregnant women with Cu level below median value, comparing with those with Cu level above median value (β = -0.08, 95%CI: -0.57, 0.42), and a similar pattern was found for EFW, although the interaction between Mo and Cu was not significant. Our data suggested an inverse association of maternal urinary Mo level with fetal AC and EFW during the second trimester of pregnancy. These associations might be stronger in pregnant women with relatively lower Cu levels.

H. Zhao, W. Wu, X. Zhang, Q. Zhu, J. Tang, H. He, G. Chen, and J. Qin,Associations between molybdenum exposure and ultrasound measures of fetal growth parameters: A pilot study, Chemosphere, 2021, 269, 128709.


Genotoxicity and mutagenicity

Genotoxicity and mutagenicity of molybdenum(VI) and iron(III) and interactions between these microelements

Background: The aim of this study was to examine the effect of iron(III) (Fe(III)) and molybdenum(VI) (Mo(VI)) and their combinations on genotoxicity, mutagenicity, pro- and antioxidant activity in BALB/3T3 and HepG2 cells. Materials and methods: The cells were cultured in media supplemented with iron chloride or molybdenum trioxide at concentrations of 200 or 1,000 mu M. Moreover, the cells exposed to a mixture of microelements: 200 mu M of iron chloride plus 1,000 mu M of molybdenum trioxide and, in the other case, supplemented with 200 mu M of molybdenum trioxide plus 1,000 mu M of iron chloride. After 24 hours of incubation, comet, micronucleus, and Ames assays were performed. Additionally, DCFDA Cellular ROS Detection Assay, TBARS Assay, SOD Assay, Catalase Assay, and Glutathione Peroxidase Assay were performed.

Results: Additions of Fe(III) at 200 mu M plus Mo(VI) at 1,000 mu M showed synergistic effect - the increased number of comets and micronuclei in both cell lines was observed. Moreover, the number of revertants increased as well. In the case of Fe(III) at 1,000 AM plus Mo(VI) at 200 mu M, the same effect was observed. Moreover, treated cells display characteristic apoptosis in comparison to control cells. Giant and multinuclear cells were observed. In all tested microelements, the increase in number of reverse mutations was observed with and without metabolic activation. The level of reactive oxygen species and malondialdehyde (MDA) in cells increased after simultaneous exposure of cells with 200 mu M iron chloride plus 1,000 mu M molybdenum trioxide. The similar results in the case of interaction of 1,000 mu M of iron chloride plus 200 mu M of molybdenum trioxide were observed. Superoxide dismutase, catalase, and glutathione peroxidase activities decrease in a statistically significant and dose-dependent way after treatment with iron chloride and molybdenum trioxide.

Conclusion: Iron (iron(III) chloride and molybdenum (trioxide)  are genotoxic and mutagenic. In our study Fe(III) and Mo(VI) show synergistic effects in genotoxicity and mutagenicity assays. Both of them can generate ROS. Moreover, Fe(III) interacts with DNA bases. These independent mechanisms can cause synergistic effects.

S. Terpilowska, and A. K. Siwicki, Genotoxicity and mutagenicity of molybdenum(VI) and iron(III) and interactions between these microelements, Trace Elements and Electrolytes, 2020, 37, 180-187.


Comparative analysis of biological effects of molybdenum(IV) sulfide in the form of nano- and microparticles on human hepatoma HepG2 cells grown in 2D and 3D models

Significance of MoS2 nanoparticles as a lubricant or drug carriers indicates the need to assess their safety. In the study we analyzed the effects of MoS2 nano- and microparticles and their internalization in vitro, using 2D and 3D culture models of human hepatoma HepG2 cell line. MoS2 micro- and nanoparticles were characterized with high resolution electron microscopy (HR-SEM), X-ray diffraction (XRD) and Energy Dispersive X-Ray Spectroscopy (EDS). The cells were exposed to a range of concentrations of the nano-and microparticles suspensions (maximum of 250 mu g/mL) for 72 h. Cell viability was assessed using WST-1 reduction test and LDH release assay. Particle internalization was analyzed using scanning transmission electron microscopy (STEM). The nanoparticles were internalized into the 2D and 3D cultured cells, in spheroids more efficiently into the outer layer. For microparticles mainly particles of less than 1 mu m in diameter underwent internalization. This process, however, did not affect cell viability as measured with the WST-1 and LDH assays. STEM observation showed well preserved integrity of the cell membrane and no apparent cytotoxic effect. Although the particles seemed to be safely sequestered in vacuoles or the cytoplasm, their fate and eventual biological effects are not certain and deserve further studies.

Z. Sobanska, K. Domeradzka-Gajda, M. Szparaga, J. Grobelny, E. Tomaszewska, K. Ranoszek-Soliwoda, G. Celichowski, L. Zapor, K. Kowalczyk, and M. Stepnik,Comparative analysis of biological effects of molybdenum(IV) sulfide in the form of nano- and microparticles on human hepatoma HepG2 cells grown in 2D and 3D models, Toxicology in Vitro, 2020, 68, 104931.



The Influence of Size and Phase on the Biodegradation, Excretion, and Phytotoxicity Persistence of Single-Layer Molybdenum Disulfide

The increasing applications of single-layer molybdenum disulfide (SLMoS2) pose great potential risks associated with environmental exposure. This study found that metallic-phase SLMoS2 with a nanoscale (4N-1T-SLMoS2, ~400 nm) and microscale (M-1T-SLMoS2, ~3.6 μm) diameter at 10~25 mg/L induced significant algal growth inhibition (maximum 72.7% and 74.6%, respectively), plasmolysis, and oxidative damage, but these alterations were recoverable. Nevertheless, membrane permeability, chloroplast damage, and chlorophyll biosynthesis reduction were persistent. By contrast, the growth inhibition (maximum 55.3%) and adverse effects of nano-sized semiconductive-phase SLMoS2 (4N-2H-SLMoS2, ~400 nm) were weak and easily alleviated after 96 h of recovery. 4N-1T-SLMoS2 (0.011 μg/h) and 4N-2H-SLMoS2 (0.008 μg/h) were quickly biodegraded to soluble Mo compared with M-1T-SLMoS2 (0.004 μg/h) and excreted by algae. Incomplete biodegradation of SLMoS2 (26.8%~43.9%) did not significantly mitigate their toxicity. Proteomics and metabolomics indicated that the downregulation of proteins (50.7%~99.2%) related to antioxidants and photosynthesis and inhibition of carbon fixation and carbohydrate metabolism contributed to the persistent phytotoxicity. These findings highlight the roles and mechanisms of size and phase in the persistent phytotoxicity of SLMoS2, which has potential implications for risk assessment and environmental applications of nanomaterials.

W. Zou, X. Li, C. Li, Y. Sun, X. Zhang, C. Jin, K. Jiang, Q. Zhou, and X. Hu,The Influence of Size and Phase on the Biodegradation, Excretion, and Phytotoxicity Persistence of Single-Layer Molybdenum Disulfide,Environ. Sci. Technol. 2020, 54, 19, 12295–12306.




Comparative analysis of biological effects of molybdenum(IV) sulfide in the form of nano- and microparticles on human hepatoma HepG2 cells grown in 2D and 3D models

Significance of MoS2 nanoparticles as a lubricant or drug carriers indicates the need to assess their safety. In the study we analyzed the effects of MoS2 nano- and microparticles and their internalization in vitro, using 2D and 3D culture models of human hepatoma HepG2 cell line. MoS2 micro- and nanoparticles were characterized with high resolution electron microscopy (HR-SEM), X-ray diffraction (XRD) and Energy Dispersive X-Ray Spectroscopy (EDS). The cells were exposed to a range of concentrations of the nano-and microparticles suspensions (maximum of 250 μg/mL) for 72 h. Cell viability was assessed using WST-1 reduction test and LDH release assay. Particle internalization was analyzed using scanning transmission electron microscopy (STEM). The nanoparticles were internalized into the 2D and 3D cultured cells, in spheroids more efficiently into the outer layer. For microparticles mainly particles of less than 1 μm in diameter underwent internalization. This process, however, did not affect cell viability as measured with the WST-1 and LDH assays. STEM observation showed well preserved integrity of the cell membrane and no apparent cytotoxic effect. Although the particles seemed to be safely sequestered in vacuoles or the cytoplasm, their fate and eventual biological effects are not certain and deserve further studies.

Z. Sobańska, K. Domeradzka-Gajda, M. Szparaga, J. Grobelny, E. Tomaszewska, K. Ranoszek-Soliwoda, G. Celichowski, L. Zapór, K. Kowalczyk, and M. Stępnik,Comparative analysis of biological effects of molybdenum(IV) sulfide in the form of nano- and microparticles on human hepatoma HepG2 cells grown in 2D and 3D models, Toxicol In Vitro, 2020, 68, 104931.




Cytotoxicity Elicited by Molybdenum Disulphide in Different Size of Particles in Human Airway Cells

The present investigation was aimed to study the cytotoxic response induced by molybdenum disulfide in nano- (MoS2-NPs) and micro- (MoS2-MPs) size of particle in human bronchial (BEAS-2B) and alveolar (A549) cells. The cells were exposed with different particle size of MoS2 in concentrations range 1-200 mu g/mL for 24, 48, and 72 h, and then the cytotoxicity assays (MTT and NRU) was performed. Afterwards, long-term toxicity was assessed by colony forming efficiency assay (CFEA) during 10 days exposure of the cells. Both MoS2-NPs and MoS2-MPs showed similar, weak cytotoxic effects on BEAS-2B and A549 cells assessed by MTT assay, that is reduction of cell viability to approx. 60-70% at concentrations of 2.5 and 5 mu g/mL. The percentage viability remained relatively constant at this level across all concentrations above 5 mu g/mL. In long-term exposure, both MoS2 inhibited colony formation in a wider range of concentrations to 200 mu g/mL. MoS2-NPs were slightly more cytotoxic than MoS2-MPs. The data suggest the low potential hazardous nature of both MoS2 tested with an indication of higher toxicity of MoS2-NPs.

L. Zapor,Cytotoxicity Elicited by Molybdenum Disulphide in Different Size of Particles in Human Airway Cells, Rocznik Ochrona Srodowiska, 2019, 21, 794-809.


Environmental etiology of gastric cancer in Iran: a systematic review focusing on drinking water, soil, food, radiation, and geographical conditions

The aim of this systematic review study was to investigate the causal relationship between environmental factors and gastric cancer (GC) in Iran. In a narrow definition, the environment includes water, soil, air, and food. This definition was the main criterion for the inclusion of articles in this study. In addition, exposure to radiation and geographical conditions were considered as less investigated environmental factors in the literatures. International (PubMed, Web of Science, ScienceDirect, Scopus, and Cochran) and national (Scientific Information Database) databases were searched for articles on GC and environmental risk factors in Iran. Twenty-six articles were found to meet the inclusion criteria after title, abstract, and full text review. Risk factors identified for GC include consumption of red meat; high fat, fried, and salted meat; smoked, salted, and fried foods; some dairy products; roasted and fried seeds; strong and hot tea; and un-piped and unchlorinated drinking water, as well as exposure to radiation, loess sediment, soft and grassy soil, soil containing low concentration of  molybdenum , and proximity to volcanos. Fresh fruits and vegetable, fresh fish, and honey consumption were recognized as protective agents. Given the risk factors identified, strategies to prevent GC would be educating people to choose a healthy diet and to cook and store food properly, providing access to safe drinking water, taking into account topographical and geographical conditions in choosing a right location to build residential areas, and regulating the use of radiation-emitting devices.


H. R. Ghaffari, M. Yunesian, R. Nabizadeh, S. Nasseri, A. Sadjadi, F. Pourfarzi, H. Poustchi, and A. Eshraghian,Environmental etiology of gastric cancer in Iran: a systematic review focusing on drinking water, soil, food, radiation, and geographical conditions, Environmental science and pollution research international, 2019 26:10487–10495 https://doi.org/10.1007/s11356-019-04493-8


Serum Trace Elements and Their Associations with Breast Cancer Subgroups in Korean Breast Cancer Patients

The relationships between serum levels of trace elements and breast cancer remain relatively unknown. In this study, we investigate serum levels of seven trace elements in Korean breast cancer patients compared to controls without breast cancer. Serum trace element levels were determined using inductively coupled plasma mass spectrometry in Korean breast cancer patients before initiation of breast cancer treatment. Korean females without breast cancer served as a control group. Trace element levels were measured in the discovery cohort (n = 287) and were validated in an independent cohort (n = 142). We further investigated possible associations between trace element levels and the presence of lymph node metastasis, distant metastasis, or triple-negative breast cancer among breast cancer patients in subgroup analyses. Serum manganese and  molybdenum  levels were significantly higher (p < 0.05) in breast cancer patients than in controls. Serum copper levels were significantly higher in breast cancer patients with distant metastasis, while selenium levels were significantly lower. Other trace elements were neither significantly different between breast cancer patients and controls nor between subgroups of breast cancer patients. Our study provides insights about the potential roles and impacts of trace elements through an assessment of the associations between trace elements and breast cancer.


R. Choi, M. J. Kim, I. Sohn, S. Kim, I. Kim, J. M. Ryu, H. J. Choi, J. M. Kim, S. K. Lee, J. Yu, S. W. Kim, S. J. Nam, J. E. Lee, and S. Y. Lee,Serum Trace Elements and Their Associations with Breast Cancer Subgroups in Korean Breast Cancer Patients, Nutrients, 2019, 11(1), 37; https://doi.org/10.3390/nu11010037


Toxicology of Molybdenum - Humans


Oxidative DNA damage mediates the association between urinary metals and prevalence of type 2 diabetes mellitus in Chinese adults

Previous publications have indicated that some metals are associated with an increased prevalence of type 2 diabetes mellitus (T2DM); however, the mechanisms remain largely unknown. This study aimed to quantify the associations of oxidative DNA damage with urinary metals and prevalence of T2DM among the general population, and further to assess the role of oxidative DNA damage in mediating the association of urinary metals with prevalence of T2DM. Diagnoses of T2DM were performed clinically or by measuring fasting levels of plasma glucose >= 7.0 mmol/L. Concentrations of urinary metals and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in 2127 participants were measured using inductively coupled plasma-mass spectrometry and high-performance liquid chromatography. Relationships among urinary metals, 8-OHdG (a biomarker for oxidative DNA damage), and prevalence of T2DM were analyzed using mediation analysis. After adjusting for covariates, we found that the log-transformed levels of urinary copper, arsenic, selenium, molybdenum, and antimony were positively associated with prevalence of T2DM. Urinary 8-OHdG was not only positively correlated with copper, arsenic, selenium, and antimony in an upwardly trending, dose-responsive manner but was also positively associated with prevalence of T2DM (odds ratio (OR): 1.95; 95% CI: 1.17-3.24). Mediation analysis estimated that urinary 8-OHdG mediated 13.22% and 8.84% of associations between prevalence of T2DM and concentrations of urinary arsenic and antimony, respectively (all P value < 0.05). Our findings suggested that urinary arsenic and antimony concentrations were associated with an increased prevalence of T2DM by a mechanism partly involving oxidative DNA damage. (C) 2018 Elsevier B.V. All rights reserved.

L. L. Xiao, Y. Zhou, J. X. Ma, W. W. Sun, L. M. Cao, B. Wang, C. M. Zhu, S. J. Yang, D. M. Wang, J. Yuan, and W. H. Chen,Oxidative DNA damage mediates the association between urinary metals and prevalence of type 2 diabetes mellitus in Chinese adults, Science of the Total Environment, 2018, 627, 1327-1333.


Systemic sclerosis and exposure to heavy metals: A case control study of 100 patients and 300 controls

Objective: This case control study assessed: 1) the relationship of systemic sclerosis (SSc) related to exposure to heavy metals; and 2) the risk of SSc related to occupational exposure in male and female patients.

Methods: From 2005 to 2008, 100 patients with a definite diagnosis of SSc were included in the study; 3 age, gender, and smoking habit matched controls were selected for each patient. All SSc patients and controls underwent detection and quantification of heavy metal traces in hair samples, using multi-element inductively coupled plasma mass spectrometry (ICP-MS).

Results: SSc patients exhibited higher median levels of the following metals: antimony (p = 0.001), cadmium (p = 0.0003), lead (p = 0.02), mercury (p = 0.02), molybdenum (p = 0.04), palladium (p < 0.0001) and zinc (p = 0.0003). A marked association between SSc and occupational exposure was further found for: 1) antimony (p = 0.008) and platinum (p = 0:04) in male patients; and 2) antimony (p = 0.02), cadmium (p = 0.001), lead (p = 0.03), mercury (p = 0.03), palladium (p = 0.0003) and zinc (p = 0.0001) in female patients

Conclusion: The results show the impact of occupational risk factors in the development of SSc for: antimony, cadmium, lead, mercury, molybdenum, palladium and zinc. Thus, occupational exposure should be systematically checked in all SSc patients at diagnosis. Finally, the association between SSc and occupational exposure may be variable according to patients' gender. (C) 2017 Elsevier B.V. All rights reserved.

I. Marie, J. F. Gehanno, M. Bubenheim, A. B. Duval-Modeste, P. Joly, S. Dominique, P. Bravard, D. Noel, A. F. Cailleux, J. Benichou, H. Levesque, and J. P. Goulle,Systemic sclerosis and exposure to heavy metals: A case control study of 100 patients and 300 controls, Autoimmunity Reviews, 2017, 16, 223-230.

[Systemic scleroderma, also called diffusescleroderma or systemic sclerosis, is an autoimmune disease of the connective tissue. It is characterized by thickening of the skin caused by accumulation of collagen, and by injuries to small arteries. https://en.wikipedia.org/wiki/Systemic_scleroderma.

Scleroderma is caused by the immune system attacking the connective tissue under the skin and around internal organs and blood vessels. This causes scarring and thickening of the tissue in these areas.

There are two main types of scleroderma: localised scleroderma – just affects the skin systemic sclerosis – may affect blood circulation and internal organs as well as the skin.



Chronic kidney disease

High prevalence of elevated molybdenum levels in pediatric CKD patients. A cross-sectional and longitudinal study

AIMS: Many of the secondary effects of high levels of molybdenum (Mo) overlap with symptoms commonly seen in pediatric patients with chronic kidney disease (CKD).
We measured plasma Mo levels and examined the relationship between Mo levels and kidney function.
MATERIALS AND METHODS: The study was carried out at the London Health Sciences Centre in London, Ontario, Canada with 36 children and adolescents 4 - 18 years of age with CKD. There were 1 - 6 trace element measurements (Mo and copper (Cu)) per patient. We studied the proportion of patients with abnormal trace element levels and the relationship between trace element levels and estimated glomerular filtration rate (eGFR), calculated using the Filler formula. Plasma Mo and Cu levels were measured using High Resolution Sector Field Inductively Coupled Mass Spectrometry. Anthropomorphic data and blood parameters were collected from our electronic chart program.
RESULTS: Median eGFR was 51 mL/min/1.73m2 (35, 75). Median Mo level was 2.00 microg/L (1.40, 2.88). 20 patients had at least one set of Mo levels above the published reference interval in either unit, and the results of 46% of the tests were above the interval. There was a strong negative correlation between the Mo levels and the eGFR (Spearman's r = -0.627, p. < 0.0001).
CONCLUSIONS: Our study suggests that pediatric patients with CKD have elevated plasma levels of Mo, which may cause secondary effects commonly associated with CKD. The elevated Mo levels in our center's catchment area may cause an accumulation of this trace element in patients with impaired renal function.

Yang, G., Belostotsky, V., Kobrzynski, M., Huang, S. S., and Yang, L.,High prevalence of elevated molybdenum levels in pediatric CKD patients. A cross-sectional and longitudinal study, Clinical nephrology, 2017 88 79-85
NHS Choices: http://www.nhs.uk/Conditions/Kidney-disease-chronic/Pages/Diagnosis.aspx
The main test for kidney disease is a blood test that's used to work out how well your kidneys are working. The test measures the levels of a waste product called creatinine in your blood. Using this result, a calculation that takes into account your age, gender and ethnic group is then done to work out how many millilitres of waste your kidneys are able to filter in a minute.This measurement is known as your estimated glomerular filtration rate (eGFR).Healthy kidneys should be able to filter more than 90ml/min. You may have kidney disease if your result is lower than this.




In vitro cytotoxicity of covalently protected layered molybdenum disulfide

Layered molybdenum disulfide (MoS2) is in forefront of materials research. MoS2 has been reported to display various unique electronic, catalytic and sensing properties. Functionalization of MoS2 is common as it can improve biocompatibility, electrochemical behaviour, catalytic performance, and sensing abilities. In this study, a cytotoxicity study of MoS2 functionalized with an organic molecule, thiobarbituric acid (TBA) was conducted. The functionalization of MoS2 with TBA (MoS2-TBA) is unique as it was reported to retain metallic 1T-type character which is important for electrochemical applications. In addition, MoS2-TBA could possibly be utilized to a wider range of applications as it can be further modified due to the presence of alcohol groups. Thus, investigating the toxicity of MoS2-TBA is essential since it has promising properties for several applications. Functionalized MoS2-TBA is expected to have different toxicity profile than non-functionalized MoS2 as several physicochemical properties may have changed after functionalization. The cytotoxicity study has been conducted via two common cell viability assays which are methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and water-soluble tetrazolium salt (WST-8) assay. Human lung carcinoma epithelial cell line (A549) was chosen for this study it is highly probable for nanomaterials to enter the lungs and interact with the body via inhalation through the respiratory tract from the environment. This study has found that MoS2-TBA has become less toxic as compared to MoS2. (C) 2018 Elsevier Ltd. All rights reserved.

N. F. Rosli, N. M. Latiff, Z. Sofer, A. C. Fisher, and M. Pumera,In vitro cytotoxicity of covalently protected layered molybdenum disulfide, Applied Materials Today, 2018, 11, 200-206

In Vivo Long-Term Biodistribution, Excretion, and Toxicology of PEGylated TRANSITION-METAL DICHALCOGENIDES MS2 (M = Mo, W, Ti) Nanosheets

With unique 2D structures and intriguing physicochemical properties, various types of transition metal dichalcogenides (TMDCs) have attracted much attention in many fields including nanomedicine. Hence, it is of great importance to carefully study the in vivo biodistribution, excretion, and toxicology profiles of different TMDCs, and hopefully to identify the most promising type of TMDCs with low toxicity and fast excretion for further biomedical applications. Herein, the in vivo behaviors of three representative TMDCs including molybdenum dichalcogenides (MoS2), tungsten dichalcogenides (WS2), and titanium dichalcogenides (TiS2) nanosheets are systematically investigated. Without showing significant in vitro cytotoxicity, all the three types of polyethylene glycol (PEG) functionalized TMDCs show dominate accumulation in reticuloendothelial systems (RES) such as liver and spleen after intravenous injection. In marked contrast to WS2-PEG and TiS2-PEG, which show high levels in the organs for months, MoS2-PEG can be degraded and then excreted almost completely within one month. Further degradation experiments indicate that the distinctive in vivo excretion behaviors of TDMCs can be attributed to their different chemical properties. This work suggests that MoS2, among various TMDCs, may be particularly interesting for further biomedical applications owning to its low toxicity, capability of biodegradation, and rapid excretion.

Hao, J., Song, G., Liu, T., Yi, X., Yang, K., Cheng, L., and Liu, Z.,In Vivo Long-Term Biodistribution, Excretion, and Toxicology of PEGylated Transition-Metal Dichalcogenides MS2 (M = Mo, W,Ti) Nanosheets, Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2017, 4, 1600160.

SYSTEMIC SCLEROSIS and exposure to heavy metals: A case control study of 100 patients and 300 controls

OBJECTIVE: This case control study assessed: the relationship of systemic sclerosis (SSc) related to exposure to heavy metals, the risk of SSc related to occupational exposure in male and female patients.

METHODS: From 2005 to 2008, 100 patients with a definite diagnosis of SSc were included in the study; 3 age, gender, and smoking habits matched controls were selected for each patient. All SSc patients and controls underwent detection and quantification of heavy metal traces in hair samples, using multi-element inductively coupled plasma mass spectrometry (ICP-MS).

RESULTS: SSc patients exhibited higher median levels of the following metals: antimony (p=0.001), cadmium (p=0.0003), lead (p=0.02), mercury (p=0.02), molybdenum (p=0.04), palladium (p<0.001) and zinc (p=0.0003). A marked association between SSc and occupational exposure was further found for: 1) antimony (p=0.008) and platinum (p=0.04) in male patients; and 2) antimony (p=0.02), cadmium (p=0.001), lead (p=0.03), mercury (p=0.03), palladium (p=0.0003) and zinc (p=0.0001) in female patients

CONCLUSION: The results show the impact of occupational risk factors in the development of SSc for: antimony, cadmium, lead, mercury, molybdenum, palladium and zinc. Thus, occupational exposure should be systematically checked in all SSc patients at diagnosis. Finally, the association between SSc and occupational exposure may be variable according to patients" gender.

Marie, I., Gehanno, J. F., Bubenheim, M., Duval-Modeste, A. B., Joly, P., Dominique, S., Bravard, P., Noel, D., Cailleux, A. F., Weber, J., Lagoutte, P., Benichou, J., Levesque, H., and Goulle, J. P.,Systemic sclerosis and exposure to heavy metals: A case control study of 100 patients and 300 controls, Autoimmunity reviews, 2017.

[Systemic sclerosis (SSc) is a multisystem autoimmune disease in which there is increased fibroblast activity resulting in abnormal growth of connective tissue. This causes vascular damage and fibrosis. Fibrosis occurs in skin, the gastrointestinal (GI) tract, heart, lungs and other internal organs. Vascular manifestations include secondary Raynaud's phenomenon, ischaemia of extremities, pulmonary arterial hypertension and renal disease. http://patient.info/doctor/systemic-sclerosis-scleroderma.]

Molybdenum Disulfide. Differences in the Toxicological Potential of 2D versus Aggregated Molybdenum Disulfide in the Lung

2D molybdenum disulfide (MoS2 ) has distinct optical and electronic properties compared to aggregated MoS2 , enabling wide use of these materials for electronic and biomedical applications. However, the hazard potential of MoS2 has not been studied extensively. Here, a comprehensive analysis of the pulmonary hazard potential of three aqueous suspended forms of MoS2 -aggregated MoS2 (Agg-MoS2 ), MoS2exfoliated by lithiation (Lit- MoS2 ), and MoS2 dispersed by Pluronic F87 (PF87- MoS2 )-is presented. No cytotoxicity is detected in THP-1 and BEAS-2B cell lines. However, Agg- MoS2 induces strong proinflammatory and profibrogenic responses in vitro. In contrast, Lit- and PF87- MoS2 have little or no effect. In an acute toxicity study in mice, Agg- MoS2 induces acute lung inflammation, while Lit- MoS2 and PF87- MoS2 have little or no effect. In a subchronic study, there is no evidence of pulmonary fibrosis in response to all forms of MoS2 . These data suggest that exfoliation attenuates the toxicity of Agg- MoS2 , which is an important consideration toward the safety evaluation and use of nanoscale MoS2 materials for industrial and biological applications.

Wang, X., Mansukhani, N. D., Guiney, L. M., Ji, Z., Chang, C. H., Wang, M., Liao, Y. P., Song, T. B., Sun, B., Li, R., Xia, T., Hersam, M. C., and Nel, A. E.,Differences in the Toxicological Potential of 2D versus Aggregated Molybdenum Disulfide in the Lung, Small (Weinheim an der Bergstrasse, Germany), 2015, 11, 5079-87.

Antioxidative and cytoprotective response elicited by molybdenum nanoparticles in human cells

Nanotechnology based therapeutics can offer an alternative platform in a wide variety of biomedical applications. Here we report novel cytotoxicity preventive potential of molybdenum nanoparticles (Mo NPs) in human breast (MCF-7) and fibrosarcoma (HT-1080) cells compromised with oxidant exposure. Physicochemical properties such as size, crystallinity, purity and band gap (an optical characteristic) of Mo NPs were characterized respectively by field emission transmission electron microscopy (FETEM), X-ray diffraction (XRD), energy dispersive spectrum (EDS) and UV-vis absorption spectroscopy. The average size of crystalline Mo NPs was found to be 35nm with a band gap of 1.4eV. Potential cytotoxicity of Mo NPs was evaluated by a battery of cell viability and oxidative stress parameters. Cell viability and oxidative stress data suggested Mo NPs to be reasonably non-cytotoxic. Cytotoxic preventive and GSH restoring potential of Mo NPs was determined against cytotoxicity and oxidative stress induced by H2O2 (and ZnO NPs) in two cells. Mo NPs significantly increased GSH level in MCF-7 and HT-1080 cells, an activity that was comparable to antioxidant N-acetyl cysteine (NAC). GSH level was increased 1.56 times in MCF-7 cells and 1.25 times in HT-1080 cells by 100mug/ml of Mo NPs relative to control cells in 24h. End-point data clearly suggest that Mo NPs significantly protected cells against cytotoxicity induced by H2O2 and ZnO (NPs) (p<0.05). Our study warrants further investigation about Mo NPs that could be exploited in myriads of nanotechnology applications.

Akhtar, M. J., Ahamed, M., Alhadlaq, H. A., Alshamsan, A., Majeed Khan, M. A., and Alrokayan, S. A.,Antioxidative and cytoprotective response elicited by molybdenum nanoparticles in human cells, Journal of colloid and interface science, 2015, 457, 370-7.

[XRD pattern consistent with Mo metal.]


Molybdate urinary: inverse association with human serum testosterone

Objective: To examine the potential associations between biomarkers of metal exposure and serum testosterone in men of reproductive age in the general US population.

Design: Cross-sectional epidemiology study with adjustment for potential confounders.

Setting: Not applicable.

Patient(s): Men recruited in the United States National Health and Nutrition Examination Survey (NHANES).

Intervention(s): Metal concentrations measured in whole blood, urine, and/or serum samples collected from 484 men.

Main Outcome Measure(s): Serum T concentration.

Result(s): Concentrations of the metals were detected in 69%-100% of the samples.

In adjusted analyses where metals were modeled as a continuous variable, we found significant inverse associations between urinary molybdenum and serum copper and serum T, whereas there were significant positive associations between blood lead and cadmium and serum T.

When metals were categorized into quartiles, analyses for serum copper and blood lead and cadmium produced significant associations in the same direction as the continuous measures.

A suggestive inverse association was observed between quartiles of urinary molybdenum and serum T, but the association was statistically significant when molybdenum was categorized into quintiles.

Significant positive associations were also observed for quartiles of blood Se and serum Zn and serum T.

Conclusion(s): These findings add to the limited human evidence that exposure to molybdenum and other metals is associated with altered T in men, which may have important implications for male health. More research is needed to confirm the findings of our study. (C) 2015 by American Society for Reproductive Medicine

Lewis, R. C. and Meeker, J. D., Biomarkers of exposure to molybdenum and other metals in relation to testosterone among men from the United States National Health and Nutrition Examination Survey 2011-2012, Fertility and Sterility, 2015, 103, 172-178.

Toxicity of Molybdenum Towards Human Beings

Tolerable daily intake

A tolerable daily intake (TDI) for molybdenum of 0.009 mg Mo /kg/ day for humans was calculated based on a toxicological risk analysis derived from a survey of the absorption, excretion, uptake, and physiological and toxic effects of molybdenum in humans and animals [Vyskocil and Viau, 1999]. The TDI was given a medium confidence rating. This TDI is more than double the upper limit of adequate intake for adolescents and adults that was derived from the Mo content of the average diet in the USA.

Vyskocil, A., Viau, C., Assessment of molybdenum toxicity in humans, Journal Of Applied Toxicology, 1999, 19, 185-192.

Toxicology of Molybdenum - Humans

Data on molybdenum toxicology are summarised in a very useful review article.

Barceloux, D.G., Molybdenum, Journal Of Toxicology-Clinical Toxicology, 1999, 37, 231-237.

See also

Gupta, U.C., Gupta,_S.C., Trace element toxicity relationships to crop production and livestock and human health: Implications for management, Communications In Soil Science And Plant Analysis, 1998, 29, 1491-1522.

We distinguish between acute toxicity and chronic, or long, term toxicity. The occurrence of acute poisoning is easy to detect since it produces obvious and often dramatic symptoms and ultimately death. Most experimental studies of molybdenum poisoning have been concerned with possible acute toxic effects. It is clear from the data summarised here that acute molybdenum poisoning in human beings is very unlikely: a massive dose would be required [National Research Council 9, 1980]. Compared with some metals used industrially (antimony, arsenic, beryllium, cadmium, chromium, lead, mercury) molybdenum is of very low toxicity [Saunders, 1956; Browning, 1969; Ashmead, 1972; Nguyen-Phu-Lieh, 1971]

National Research Council 9 1980, Molybdenum in: Mineral Tolerance of Domestic Animals, 328. National Academy of Sciences,
Saunders, W. B., Handbook of Toxicology, London, 1956.
Browning, E., Toxicity of Industrial Metals, 2nd edn., 1969, Butterworths, London.
Ashmead, H., J. Appl. Nutrition, 1972, 24, 8.
Nguyen-Phu-Lieh, Aliment. Vie, 1971, 59, 104.

There have been no reports of accidental deaths due to molybdenum poisoning in industry. More relevant in terms of environmental considerations are possible effects on human beings of long exposure to low concentrations of molybdenum compounds. Experience with workers exposed to molybdenum compounds indicates that molybdenum does not have long term chronic toxic effects. However, in making such assessments it would be helpful to know what to look for. Herein is the importance of a knowledge of the physiological and pathological effects of molybdenum compounds. Finally we have to assess the danger or otherwise of molybdenum as a general environmental pollutant. At current levels and in view of its low toxicity molybdenum is not a source of environmental pollution; but it should be noted that some animal species, especially cattle and sheep, are more susceptible to molybdenum poisoning than human beings. Chronic exposure defined as the administration of a total single dose of 2.365 to 24.497 microg of molybdenum results in a rise in the number of death rates from 14.2% to 57.2% in exposed animals the most common symptom of chronic exposure being acute anemia [Caujolle and Pham Hu Changh, 1967]. In chronically exposed cattle the addition of copper ions can result in a complete recovery from the signs of molybdenum intoxication.

Caujolle, F., Pham Hu Changh. (1967), Agressologie, 8, 265-273.

By extrapolation from animal experiments massive doses of molybdenum compounds would be required to produce acute molybdenum poisoning in human beings and so acute poisoning is unlikely. What is more important is the problem of whether continued exposure to low concentrations of molybdenum compounds causes subtle physiological changes. Such changes would be difficult to detect and we are not aware of any experimental investigations with human beings. Experience in the molybdenum mining and refining industries suggests that molybdenum compounds are not industrial health hazards [Saunders, 1956; Browning, 1969; Ashmead, 1072; Nguyen-Phu-Lieh, 1971].

Saunders, W. B., Handbook of Toxicology, London, 1956.
Browning, E., Toxicity of Industrial Metals, 2nd edn., 1969, Butterworths, London.
Ashmead, H., J. Appl. Nutrition, 1972, 24, 8.
Nguyen-Phu-Lieh, Aliment. Vie, 1971, 59, 104.

It is clear from animal experiments that molybdenum does have physiological effects and can affect the balance of other trace elements. In experimental animals the harmful effects of molybdenum are most apparent in the liver and kidneys. These organs in human beings as in various animals have consistently higher concentrations of molybdenum than other body organs [Underwood, 1962; Kolomiitseva et al., 1968; Schroeder et al., 1970]. So it is likely that harmful effects of exposure to molybdenum compounds will be most apparent in the liver and kidneys. Also molybdenum may have a harmful effect on bones.

Underwood, E. J., Trace Elements in Human and Animal Nutrition, 2nd Ed.,1962, Academic Press, London.
Kolomiitseva, M. G., Polonskaya, M. N. and Osipov, G. K., Mikroelem. Sel. Khoz. Med., 1968, 4, 183.
Schroeder, H. A., Balassa, J. J. and Tipton, I. H., J. Chronic Dis, 1970, 23, 481.

Dust and fumes of molybdenum trioxide and molybdates are likely to present a greater hazard than molybdenum disulfide. The observation that sulfide enhances the toxicity of soluble molybdenum compounds suggests the desirability of exercising care in handling and use of soluble molybdenum sulfur compounds.

Some studies of apparent effects of molybdenum on human beings are summarised below. The discussion in this and the following section is based on abstracts of Russian papers of which we have not been able to obtain the originals and so cannot assess the validity of the results. This work is widely quoted but its value and relevance is doubtful (see below). Thus we are unable to give the concentrations of molybdenum encountered; but they are presumably greater than the maximum permissible values subsequently adopted by Russia (U.S.S.R.): 4 mg/m3 for soluble compounds and 6 mg/m3 for insoluble compounds. It is also not certain that the effects were, in fact due to molybdenum.

Absorption and excretion of molybdenum

In humans, absorption of molybdenum after oral intake is in the range of 28-77% and urinary excretion is 17-80% of the total dose. Molybdenum compounds have low toxicity towards humans but there are not enough data to calculate any dose-response or dose-effect relationships. Because molybdenum toxicity is associated with copper intake or depleted copper stores in the body, humans who have an inadequate intake of dietary copper or some dysfunction in their copper metabolism that makes them copper-deficient could be at greater risk of molybdenum toxicity.

However, in rats and mice molybdenum adversely affected reproduction and foetal development. were found to be critical effects observed. The 'no observed adverse effect' level was 0.9 and the 'lowest observed adverse effect' level 1.6 mg Mo/ kg/ day.

In studies with students the no observed adverse effect level for students was 8 microg/kg/d [EPA, 1979].

USEPA. Human Health Effects of Molybdenum in Drinking Water. Cincinnati, Ohio: US Environmental Protection Agency, EPA-600A-79-006, 1979.

Young girls aged 7-9 years given 75 microg Mo/d revealed elevated levels of molybdenum in the urine, but no specific adverse effects [Miller et al., 1959].

Miller, R.F., Price, N.O., Engel, R.W., The microelement (Al, Mn, Cu, Molybdenum, and Co) balance of 7-9-year-old girls, Fed. Proc. 1959, 18, 538.

Molybdenum in urinary calculi

Metals concentrations were determined in 110 urinary calculi samples from hospital patients in Jordan using X-ray fluorescence (XRF) and atomic absorption spectroscopy (AAS). Twenty-one calculi were pure calcium oxalate (CaOax), 29 were mixed calcium oxalate/uric acid, 23 were mixed calcium oxalate/phosphate (apatite), 25 were phosphate calculi (apatite/struvite), five were mixed calcium oxalate monohydrate/struvite, four were urate calculi (mixed ammonium acid urate/sodium acid urate) and three were pure cystine calculi. Mean metal concentrations were: Ca 48.18, Na 1.56, K 0.9, Mg 3.08, Fe 1.17, Al 0.49, Zn 0.7, Cu 0.19, Mn 0.029, P 10.35, S 1.88, Sr 0.306, Mo 0.2, Cr 0.146, Co 0.05, Ni 0.014 %.

It is noteworthy that the concentration of molybdenum in the urate and cystine calculi (0.65, 0.58 wt-%) is ten-fold greater than the concentration in the other calculi, a selectivity effect not found for the other metals and reflecting possibly the involvement of molybdenum in urate production via the molybdoenzyme xanthin oxidase.

Abboud, I. A., Concentration effect of trace metals in Jordanian patients of urinary calculi, Environmental Geochemistry and Health, 2008, 30, 11-20.

Hepatotoxicity: Urinary heavy metals and associated medical conditions in the US adult population

Health effects of heavy metals have been widely investigated, but further evaluation is required to comprehensively delineate their toxicity. Using data from the 2007-2008 National Health and Nutrition Examination Survey, a multivariate logistic regression analysis was performed on 1,857 adults to examine the relationship between urinary heavy metals and various medical conditions.

Cardiovascular diseases were correlated to cadmium (OR: 4.94, 95% CI: 1.48-16.56) and lead (OR: 5.32, 95% CI: 1.08-26.21).

Asthma was related to tungsten (OR: 1.72, 95% CI: 1.15-2.59) and uranium (OR: 1.52, 95% CI: 1.01-2.28).

Hepatotoxicity was associated with molybdenum (OR: 3.09, 95% CI: 1.24-7.73) and uranium (OR: 4.79, 95% CI: 1.74-13.19).

Surprising inverse relationships occurred for excessive weight with lead (OR: 0.72, 95% CI: 0.52-0.98), reduced visual acuity with cobalt (OR: 0.65, 95% CI: 0.44-0.95) and cesium (OR: 0.52, 95% CI: 0.35-0.77).

This study supports some previous evidence of potential relationships and provides insights for future research

Mendy, Angelico, Gasana, Janvier, and Vieira, Edgar Ramos, Urinary heavy metals and associated medical conditions in the US adult population, International Journal of Environmental Health Research, 2012, 22, 105-118.

[Hepatotoxicity: chemically-driven liver damage

CI: cumulative incidence. A measure of frequency, as in epidemiology where it is a measure of disease frequency during a period of time. Cumulative incidence is calculated by the number of new cases during a period divided by the number of people at risk in the population at the beginning of the study.

OR: Odds Ratio. The odds ratio provides a measure of the strength of relationship between two variables. The OR ranges in value from 0 to infinity. Values close to 1.0 indicate no relationship between the exposure and the outcome. Values less than 1.0 suggest a protective effect, while values greater than 1.0 suggest a causative or adverse effect of exposure (http://www.answers.com/topic/odds-ratio).]

Effect of molybdenum-containing dusts on the lungs

The effect on the lungs of 503 workers in a Russian powder metallurgy plant, of exposure to dusts containing molybdenum has been described [IOG, 1965]. The inspiratory, expiratory and vital capacities were determined. Reduced expiratory capacity was observed in 17.8% of molybdenum workers, 12.9% of sulphuric acid workers and 7.2% of sintered carbide workers. A pathological ratio of expiratory and inspiratory capacities, which may be an indication of bronchospasm, was encountered with a comparatively greater frequency among molybdenum workers than among those working in other departments. The nature of the molybdenum to which the workers were exposed was not clear but was probably molybdenum trioxide fume and molybdenum metal powder.

IOG, Referativny Zhurnal-Metallurgiya, 1965, IOG153, 154.

Elevated metal concentrations in the CF airway correlate with cellular injury and disease severity
Bio-active trace metals have been identified in respiratory tract secretions of subjects with lung disease and may potentially influence bacterial virulence, inflammation and disease severity.
We measured a diverse range of metal ions in sputum samples from subjects with CF [cystic fibrosis] and non-CF bronchiectasis (NCFB) compared to healthy controls and examined their relationship to airway inflammation, disease severity and the presence of bacterial pathogens.

We studied 45 subjects with CF, 8 with NCFB and 8 healthy controls. Metal concentrations were measured in sputum supernatant by inductively-coupled plasma mass spectrometry and correlated with sputum inflammatory cell counts, lactate dehydrogenase (LDH) and interleukin (IL)-8 concentrations, atmospheric particulate matter, lung function, clinical status and participant demographics.

Sputum from subjects with CF and NCFB contained increased concentrations of magnesium, calcium, iron and zinc. Metal ion concentrations correlated positively with LDH levels. The concentrations of magnesium, iron and zinc positively correlated with IL-8.

A sub-group of CF subjects with severe lung disease demonstrated increased sputum molybdenum concentrations.

Elevated concentrations of sputum metal ions appear to be associated with cell/tissue necrosis and inflammation in subjects with CF and NCFB.

Sputum molybdenum concentrations may be a biomarker of severe CF airway disease.
(c) 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved

Smith, D. J., Anderson, G. J., Bell, S. C., and Reid, D. W., Elevated metal concentrations in the CF airway correlate with cellular injury and disease severity, Journal of Cystic Fibrosis, 2014, 13, 289-295.
[Bronchiectasis is a long-term condition where the airways of the lungs become abnormally widened, leading to a build-up of excess mucus.]

Effects on respiratory health of long-term exposure of workers to molybdenum (and other metals)

The following is a detailed summary of a recent study of exposure to MoO3 fumes.

The effects of long term exposure to different species of chromium on the respiratory health of workers after 23 years of mean exposure have been assessed.and compared with the results of a previous study of 5 years earlier

Stages in process when molybdenum is present

(1) Steel melting shop

Molybdenum is used in the steel melting shop when various types of scrap and alloying materials such as nickel and molybdenum are combined with ferrochrome. These raw materials are melted in a closed arc furnace and blown with oxygen (to keep silicon to the required levels). Carbon content of the steel is lowered to the required level in an argon-oxygen decarbonisation converter.

(2) Continuous casting machine

Steel from (1) flows from the ladle via an intermediate holding basin to water cooled copper moulds and then to the casting blow. After straightening, the slabs are moved and cut to ordered length by flame cutting.

Slabs are then rolled in the hot rolling mill consisting of a walking beam furnace, a roughing mill and a Steckel-type finishing mill. Hot rolled strips are welded to form long uniform strips which are then annealed and pickled. Gas fired furnaces, shot blasting units and electrolytic pickling units. At the first stage of latter neutral Na2SO4 is used, then HNO3 and HF.

(3) Cold rolling mill

Finally cold rolling mill workers were selected as the control group as exposure levels to chromium or dust presumably from any source, were extremely low or non-existent.

Molybdenum levels in the steel melting shop (mg m-3)
Personal samplesStationary samples
Median 0.0003 (6) Median 0.0006
Maximum 0.0023 Maximum 0.0040

Measurements were only available for the current study in 1999.

These levels were considered to be low.

Methods used to assess the effects of exposure.

Questionnaire based on one used by the wool textile industry by the Edinburgh Study Group and the definitions from the MRC questionnaire.

Information gathered:

Personal characteristics, occupational history, respiratory symptoms, smoking habits, medication and family history re. allergic and pulmonary disease.

Cough, phlegm, shortness of breath, wheeze. Rhinitis, eye irritation.

Criteria: Cough lasting >3 months and improving after >1 weeks holiday were considered work related.

Dyspnoea (laboured breathing) occurring twice a month caused or worsened by impurities in the work environment or during a work shift but becoming better after a weeks holiday regarded as work related.

Standard lung function measurements made and results separated for smokers and non smokers. Chest X-rays results classified according to modified classification of the ILO.


The results were given from 4 groups according to exposure to different chromium compounds:

Cr6+ [furnace department of the ferrochromium plant, (before involvement of Mo) and the steel melting shop where the alloy with Ni and Mo is formed]; 104 participants.

Cr3+ (sintering and crushing departments); 68 participants. (initial stage of process, no Mo involved).

Chromite (FeO. Cr2O3), chromite mine; 31 participants (no Mo involvement).

a control group; 81 participants.

Exposure to molybdenum was realistically only likely in the group 1 participants.

Group 1 results

Respiratory symptoms were not significantly different at P < 0.5, exposure vs control group in Fisher’s exact test for 1998 participants.

Results for the lung tests were virtually identical between exposed and control groups for non-smokers.

Significant differences at P < 0.05 were found in the smokers group compared with the control group for the diffusing capacity and specific diffusing capacity including those corrected for Hb. (Values for Groups 2 and 3 were not significantly different and in fact were almost identical with those from the control group).

Radiographs. The profusion of small opacities had progressed from 1993 in just 3 workers, one of which was in the Cr6+ group.

Field emission scanning electron microscope analysis

Aerosols from the steel melting shop were predominately metal alloys. No pure Cr or Ni particles were observed – Mo not mentioned. (Most of the particles had an iron oxide or iron core surrounded by Cr and Ni as alloys and silicates and oxides).

Conclusions and risk assessment

Any evidence implying risk from molybdenum is very low. Any results which might possible be associated with molybdenum are embedded in the results from the Cr6+ group. The only significant results were the lung function tests for diffusing capacity in the smokers group. However, they could not just be attributed to smoking since they were not significant in the other groups. The causal effect was not established and these results were not discussed.

The stated final conclusion was that long exposures (ca 23 years) in modern ferrochromium and stainless steel production with low exposures to dusts and fumes containing chromium compounds, nickel and molybdenum do not lead to respiratory changes detectable by lung function tests or radiography. A slight increase was noted in respiratory symptoms without deterioration of lung function for the Cr3+ workers. The company had found no new cases of asthma, cancer or pneumoconiosis.

There were no associations given resulting from the presence of molybdenum.

Huvinen, M., Uitti, J., Oksa, P., Palmroos, P., and Laippala, P., Respiratory health effects of long-term exposure to different chromium species in stainless steel production, Occupational Medicine-Oxford , 2002, 52, 203-212.

Effect of molybdenum on the nervous system

The state of the nervous systems of workers in the Russian Elektronzinc plant was examined [IOG , 1965; Eolyan, 1965]. Olfactometric examination showed that 93.5% of the workers had increased thresholds to parasympathicotropic olfactory material. The same group of workers had reduced thresholds (52.6-64%) to sympathicotropic olfactory material. The olfactory thresholds for both olfactory materials increased after work. Objective symptoms of functional impairment of the nervous system were observed in 45% of the patients. Only 34.4-47.4% showed normal oculocardiac reflex. This report indicates the need for more research on the effect of molybdenum on the nervous system. (Note, however, that the technique of testing for long-term chronic poisoning by means of subtle changes in the conditioned reflex response has been criticised [Anon, 1971]. Also, it is not clear whether only molybdenum was involved.) The Russian workers were exposed for long periods without adequate protection to exceptionally high levels of molybdenum-containing dusts, but whether the symptoms were due solely to molybdenum is not determined. No such symptoms have ever been reported from molybdenum mining and refining plants. Moreover, molybdenum disulfide is nontoxic even at high concentrations.

IOG, Referativny Zhurnal-Metallurgiya, 1965, IOG153, 154.
Eolyan, S. L., Zh. Eksp. Klin. Med., 1965, 5, 70 (a translation of this paper may be obtained from P.C.H.M.)
Anon. Chem. and Eng. News, 1971.

Another paper [Eolyan, 1965] reports the effects on workers of exposure to molybdenite during ore crushing and loading operations in a copper-molybdenum extraction plant. Five-hundred workers distributed between the mine and the crushing plant were examined. The dust concentration to which the workers were exposed is not given but is described as having exceeded the "permissible concentration" (presumably ca 5 mg Mo/m3) by between 10 and 100 times. Various physical and nervous symptoms were reported and also an increase of uric acid in the blood. No symptoms of the type described in this reference have ever been reported from other molybdenum mining and refining plants and it seems that the Russian workers were exposed without adequate protection to high levels of molybdenum-containing dusts for long periods.

Eolyan, S. L., Zh. Eksp. Klin. Med., 1965, 5, 70 (a translation of this paper may be obtained from Philip Mitchell)

Mutagenic, carcinogenic and teratogenic effects

Reactive-oxygen-species-mediated Cdc25C degradation results in differential antiproliferative activities of vanadate, tungstate, and molybdate in the PC-3 human prostate cancer cell line

The differential antiproliferative effects of vanadate, tungstate, and molybdate on human prostate cancer cell line PC-3 were compared and the underlying mechanisms were investigated.

The results demonstrate that all of the three oxoanions can cause G2/M cell cycle arrest, which is evidenced by the increase in the level of phosphorylated Cdc2 at its inactive Tyr-15 site. Moreover, even if the difference in cellular uptake among the three oxoanions is excluded from the possible factors affecting their antiproliferative activity, vanadate exerted a much more potent effect in PC-3 cells than the other two oxoanions.

Our results also reveal that reactive oxygen species (ROS)-mediated degradation of Cdc25C rather than Cdc25A or Cdc25B is responsible for vanadate-induced G2/M cell cycle arrest.

We propose a possible mechanism to clarify the differential effect of the three oxoanions in biological systems beyond just considering that they are structural analogs of phosphate. We suggest that ROS formation is unlikely to be involved in the biological function of tungstate and molybdate, whereas the redox properties of vanadium may be important factors for it to exert pharmacological effects. Further, given the evidence from epidemiology studies of the association between diabetes and prostate cancer, the possibility of vanadate as a good candidate as both an antidiabetic and an anticancer agent or a chemopreventive agent is indicated

Liu, T. T., Liu, Y. J., Wang, Q., Yang, X. G., and Wang, K., Reactive-oxygen-species-mediated Cdc25C degradation results in differential antiproliferative activities of vanadate, tungstate, and molybdate in the PC-3 human prostate cancer cell line, Journal of Biological Inorganic Chemistry, 2012, 17, 311-320.

[Cdc25C: a gene which plays a key role in the regulation of cell division. The encoded protein is a tyrosine phosphatase. It directs dephosphorylation of cyclin B-bound CDC2 (CDK1) and triggers entry into mitosis [cell (nucleus) division].

Antiproliferative: a substance used to prevent or retard the spreadof cells, especially malignant cells, into surrounding tissues.]


Two epidemiological surveys conducted in 1971 in Colorado, USA, revealed differences in the molybdenum intake but no evidence that these differences were related to cancer incidence [Breise, 1976]. The comparatively high tolerance of non-ruminants for molybdenum and the interrelationship between copper, sulfate and molybdenum has been well demonstrated in ruminants. Studies on carcinogenic effects provided suggestive evidence that neither very low or very high intakes of molybdenum presented mutagenic, carcinogenic, or teratogenic hazards.

Breise. F. W., , in: Molybdenum in the Environment ,Chappell, W. R., and Petersen, K. K. (eds.), Vol. 1, Chap. 19. Marcel Dekker, New York.

The relation between lung cancer and exposure to industrial carcinogens in the Antwerp region of Belgium was investigated by questionnaires to male lung cancer patients and controls [Droste et al., 1999.]..Exposure was assessed by self report and by job-task exposure matrix. There was an excess risk of lung cancer among workers in manufacturing metal goods (e.g., welders), transport equipment (other than automobiles) (e.g., shipyard workers) and transport support services (e.g., dockers). Assessment of exposure to specific carcinogens resulted in associations of chromium, mineral oils and molybdenum with lung cancer. The authors comment that theirs is the first study reporting a significant association between occupational exposure to molybdenum and lung cancer. There are methodological problems in this type of study, which are fully discussed in the paper, in particular job descriptions and self assessment. We have also the familiar problem of attempting to equate a (not very strong) statistical correlation with a causal relationship. More work is needed, for example, to demonstrate (or not) that the lung cancer patients allegedly exposed to molybdenum do in fact have higher molybdenum lung levels than normal and display other symptoms of exposure to molybdenum.

Droste, J.H.J., Weyler, J.J., Van Meerbeeck, J.P., Vermeire, P.A., Van Sprundel, M.P., Occupational risk factors of lung cancer: a hospital based case-control-study, Occup. Environ. Med., 1999, 56, 322 - 327.

Potential chemical mutagens may be screened by the rec-assay method [Nishioka, 1975]. Differential growth sensitivities to drugs in wild and recombination-deficient strains of Bacillus subtilis are measured. When a compound is more inhibitory for Rec- than for Rec+ cells (described as a positive rec-assay or rec-effect) mutagenicity based on its DNA-damaging capacity is suspected. Cells deficient in the repair capacity of DNA lesions are usually killed much more by any DNA-damaging agent than wild cells. The difference between the inhibition zones for Rec+ and Rec- cells may be due to the magnitude of the cellular repair. The compounds potassim dichromate, K2CrO7, ammonium heptamolybdate, (NH4)6Mo7O24.4H2O, and sodium arsenite (NaAsO2) were rec-assay positive and so reported as possible mutagens. Each culture (2.5*107colony-forming cells) was treated with metal solution (0.05M, 0.05 ml) and growth inhibition determined in an agar gelled nutrient broth. Mutation induction experiments used 3 strains of E. Coli possessing different DNA repair capacities. The abilities of the compounds to induce reversions in E. Coli Trp- strains possessing different DNA repair pathways were determined. The strain (CM571) carrying the recA- was hardly mutable by any of the sodium arsenate, potassium dichromate and ammonium heptamolybdate. It is difficult to conclude from this paper that ammonium heptamolybdate is mutagenic. There are a number of inconsistencies. The suggestion that the apparent mutagenicity of dichromate and heptamolybdate is due to their common 6+ oxidation state and their oxidising ability is not tenable. Cr(VI) is strongly oxidising and is reduced to Cr(III) by sulfite; Mo(VI) is not strongly oxidising.The paper reports a decrease of Bacillus subtilis growth inhibition of dichromate after reduction with sodium sulfite. The observation that chromium(III) chloride is not inhibitory is consistent with this result (Cr(III) is formed by reduction of Cr(VI)). Similarly MoCl5 is not inhibitory. However, potassium permanganate, a stronger oxidising agent that dichromate, is not inhibitory whereas Mn(II) compounds are. Sodium arsenite (As(III) is more inhibitory than sodium arsenate (As(V)).

The effect of sulfite on dichromate inhibition is difficult to understand. Stoichiometric reduction requires 3SO32-/Cr2O72-. In this experiment where this ratio is only 0.3 (Table II) the rec-effect is the same as for a ratio of 3. We would expect the effect at the 0.3 ratio to be little different from the effect with no sulfite. It should also be noted that reduction of dichromate by sulfite requires acidic conditions, not apparently used according to the description in the paper (aqueous solutions of dichromate and sulfite were mixed) and apparently in some cases precipitates were produced.

Speciation in the nutrient broth is a problem. If the pH (not stated) is near neutral part, at least, of the supplied heptamolybdate would be in equilibrium with molybdate. In the presence of phosphate we might expect some phosphomolybdate. So the nature of the species interacting with the bacteria is uncertain. This is even more so for MoCl5 which would hydrolyse (vigorously) and its solution would oxidise in air (probably giving Mo blue under the conditions of the experiment).

There are too many uncertainties and inconsistencies in this paper for the results to be accepted as definitive proof that heptamolybdate is mutagenic.

Nishioka, H., Mutagenic activities of metal compounds in bacteria, Mutation research, 1975, 31, 185-189.

The cytotoxicity of commercially pure Nb and Mo metals and Nb-Mo alloys was tested in a 72 h direct contact test [Pypen et al., 1998]. Compared to a negative control Nb was non-toxic, but Mo was moderately toxic. None of the powder metallurgically produced materials were toxic. Neither differences in molybdenum concentration, nor in porosity of the samples, due to different production routes, had any influence on the toxicity of the materials. Mo powder is moderately toxic, however, as an alloying element it is non- toxic.

Pypen, C.M.J.M., Dessein, K., Helsen, J.A., Gomes, M., Leenders, H., DeBruijn, J.D., Comparison of the cytotoxicity of molybdenum as powder and as alloying element in a niobium-molybdenum alloy, Journal Of Materials Science-Materials In Medicine, 1998, 9, 761-765.

The cytotoxicity of molybdenum has been investigated in relation to the release of Mo (and other metals) from alloy dental, knee and hip inserts [Okazaki et al., 1998].. Mo metal particles were stired with simulated biological fluids and then separated by centrifuging. The growth rates of cells (V79 cells taken from the lungs of Chinese hamsters, murine fibroblast L929 and murine osteoblast-like MC3T3-E1 cells). Growth inhibition due to Mo was much less than inhibition due to other metals (Fe, Ni, Co) at comparable concentrations. For Mo the relative growth ratio of MC3T3-E1 cells started to decrease at Mo > 10 ppm compared with 1 - 2 ppm for the other metals. Mo is not cytotoxic.

Possible Effects of Metallosis on Spermatozoal Apoptotic Genes Expression in Individuals with Intramedullary Nailing Prosthesis

Seminal quality could be affected by metallosis caused by intramedullary nailing (IMN).
Our objectives were to estimate metal ion levels in the seminal plasma of subjects with IMN, to determine their effects on semen parameters and on spermatozoal apoptotic gene expression, and to determine whether these expressed genes could be used as candidate biomarkers of seminal deterioration in individuals with IMN or not.
Semen samples were collected from 60 subjects with IMN and 30 age-matched healthy controls. Seminal plasma contents of cobalt (Co), chromium (Cr), and molybdenum (Mo) were assayed. Spermatozoal Bcl-2 and Bax gene expressions were determined.

Studied semen parameters were significantly lower in subjects with IMN for a parts per thousand ≥5 years in relation to controls while the concentrations of Co, Cr, and Mo in the seminal plasma samples were significantly higher.

There were significantly lower spermatozoal Bcl-2 expression, higher Bax expression, and lower Bcl-2/Bax ratio in subjects with IMN for a parts per thousand ≥5 years than in controls.

In subjects with IMN for a parts per thousand ≥5 years, receiver operating characteristic (ROC) curve analysis of studied gene expressions and Bcl-2/Bax ratio were done showing priority of the ratio with 86.7 % sensitivity, 100 % specificity, 100 % positive predictive value, and 93.8 % negative predictive value at cutoff values a parts per thousand ≤0.777.

Co, Cr, and Mo metals are found at high concentrations in the seminal plasma of individuals with IMN leading to increased spermatozoal apoptotic activity. Spermatozoal Bcl-2/Bax ratio could be used as a candidate biomarker of reproductive disorders in individuals with intramedullary nailing

Elsamanoudy, A. Z., Shaalan, D., Gaballah, M. A., El Atta, H. M. A., and Helaly, A. M. N., Possible Effects of Metallosis on Spermatozoal Apoptotic Genes Expression in Individuals with Intramedullary Nailing Prosthesis, Biological Trace Element Research, 2014, 158, 334-341.
[Metallosis, or metal poisoning, is caused by toxic metal levels in the blood and is a complication of some metal-on-metal hip implants.
Intramedullary nail (IM nail) or inter-locking nail is a metal rod forced into the medullary cavity of a bone used to treat fractures of long bones of the body.]

Cytotoxicity of molybdenum(II) compounds

A series of allyl molybdenum [(eta(3)-C3H5)Mo(CO)2L2Cl], [(eta(3)-C3H4COOMe)Mo(CO)2L2Br], cyclopentadienyl molybdenum [(eta(5)-C5H4R)Mo(CO)2L-2][BF4] (R = H, 4-MeOC6H4CH2, 3,4,5-(MeO)3C6H2CH2), indenyl molybdenum [(eta(5)-C9H6R)Mo(CO)2L-2][BF4] (R = H, 4-MeOC6H4CH2) and cyclopentadienyl tungsten compounds [(eta(5)-C5H5)W(CO)2L-2][BF4], where L-2 is N,N'-chelating ligand, were synthesized and characterized. The in vitro assay on human leukemia cells MOLT-4 has shown that the substitution in the p-ligand has lower effect on cytotoxicity than exchange of the N,N'-chelating ligand. Nevertheless, even this modification can lead to considerable enhance of cytotoxicity as was evidenced on the series of the indenyl molybdenum(II) compounds. (C) 2012 Elsevier B. V. All rights reserved.

Honzicek, Jan, Vinklarek, Jaromir, Padelkova, Zdenka, Sebestova, Lucie, Foltanova, Karolina, and Rezacova, Martina, The effect of substitution on the cytotoxicity of molybdenum(II) and tungsten(II) compounds, Journal of Organometallic Chemistry, 2012, 716, 258-268.
Okazaki, Y., Rao, S., Asao, S., Tateishi, T., Effects of metallic concentrations other than Ti, Al and V on cell viability, Materials Transactions Jim, 1998, 39, 1070-1079.

Molybdenum trioxide is used in metallurgical processes, in cosmetics as a pigment, and in a contact lens solution, yet limited information is available on molybdenum genotoxicity [Titenko-Holland et al. 1998]. The micronucleus (MN) assay in human lymphocytes and mouse bone marrow and the dominant lethal assay in mice were used to assess the genotoxic effects of ammonium molybdate (0.1 - 2mM) and sodium molybdate (0.1 - 5 mM) in vitro and in vivo. Ammonium molybdate was more potent than sodium molybdate in causing a dose-dependent decrease in viability and replicative index and an increase in MN formation in binucleated lymphocytes (P < a 0.001). A dose-response in both kinetochore-positive MN (caused by chromosome lagging) and kinetochore-negative MN (associated with chromosome breakage) was observed. Two doses of sodium molybdate, 200 and 400 mg/kg, were assessed in the bone marrow MN assay in mice (two i.p. injections 24 and 48 h prior to euthanasia). A modest but statistically significant increase in MN frequency in polychromatic erythrocytes was observed (P < 0.05). The same treatment protocol was used to analyze dominant lethality. A dose-dependent increase in postimplantation loss represented mostly by early resorptions was observed the first week after treatment (P = 0.003). These preliminary data suggest that sodium molybdate induces dominant lethality at the postmeiotic stage of spermatogenesis. Molybdenum salts produced moderately positive genotoxicity at relatively high doses both in vitro in human cells and in vivo in mice.

Titenko-Holland, N., Shao, J.S., Zhang, L.P., Xi, L.Q., Ngo, H.L., Shang, N., Smith, M.T., Studies on the genotoxicity of molybdenum salts in human cells in vitro and in mice in vivo, Environmental And Molecular Mutagenesis, 1998, 32, 251-259.

Wear debris from joint replacements - molybdenum not mutagenic

Joint replacements liberate soluble and particulate wear debris from their surfaces. Metal ions are liberated into the blood and excreted in the urine. Particulate wear debris is systemically disseminated to local and distant lymph nodes, the liver and the spleen. The risks of immune reactions include hypersensitivity, toxicity, carcinogenesis and mutagenicity.

Wear debris was extracted from 21 worn hip and knee replacements. Its mutagenic effects were tested on human cells in tissue culture using the micronucleus assay and fluorescent in situ hybridisation standard mutagenicity tests.

There was a statistically significant and linear dose relationship between the number of micronuclei and the amount of wear debris.

The slope of the plot of the induction of micronuclei versus the dose of wear debris in vitro was taken as a measure of the relative activity of wear debris in inducing micronuclei. The slope is thus a measure of the effectiveness of a given dose of wear debris to induce micronuclei. The combination cobalt, chromium, nickel and molybdenum in the wear debris correlated with the slope of the total micronucleus induction with increasing dose of wear debris. The results show that wear debris can damage chromosomes in a dose-dependent manner which is specific to the type of metal. The results from studies in vitro correlate with those in vivo and suggest that the wear debris from a worn implant is at least partly responsible for the chromosomal damage which is seen in vivo.

The results for the combination cobalt, chromium, nickel and molybdenum are pertinent to assessing the mutagenic effect, if any, of molybdenum. The debris with the highest molybdenum was one of the least effective in inducing micronuclei. We can extract from the data in the paper the micronucleus induction slopes for cobalt, chromium, nickel and molybdenum as a function of the mole fraction of each element. For chromium, cobalt and molybdenum the dose relationship was horizontal, i.e. there was no specific metal induced formation of micronuclei by these metals. For nickel micronucleus induction slope increased with nickel mole fraction correlating with the increase due to total metal. It appears from these tests that molybdenum is not mutagenic.

Daley, B., Doherty, A. T., Fairman, B., and Case, C. P., Wear debris from hip or knee replacements causes chromosomal damage in human cells in tissue culture, Journal of Bone and Joint Surgery-British Volume, 2004, 86B, 598-606.

Cytotoxicity and cell growth inhibition studies were carried out for five cobalt(II) complexes and five molybdenum(VI) complexes. The cobalt complexes were binuclear complexes with a macrocyclic tetraaza ligand and acetylacetonate derivatives. The molybdenum complexes were dithiocarbamates, [MoO2(R2NCS2)2]. The cobalt complexes were tested in two leukemia cell lines: chronic myelogenic leukemia (K562) and human promyelocytic cell line (U937). They had relatively high toxicity in K562 cells and a relatively low cytotoxicity in U937 cells. as assessed by both MTT and Trypan Blue assays. The five molybdenum complexes were tested in human promyelotic U937 cell line and had high toxicity, 50–60% cell death over 72 hours.

Comment. The molybdenum complexes are not the same chemically as the cobalt complexes so strictly Mo is not being compared with Co. The Mo complexes were dissolved in methanol and introduced into the cells in solution in methanol. In a control test methanol was found 'not to have high toxicity on its own'.Since the Mo complexes are dithiocarbamates and dithiocarbamate could be released in the cell it is possible that dithiocarbamate is the source of the toxicity. According to Burkitt et al. (Burkitt, M. J., Bishop, H. S., Milne, L., Tsang, S. Y., Provan, G. J., Nobel, C. S. I., Orrenius, S., and Slater, A. F. G., Dithiocarbamate toxicity toward thymocytes involves their copper-catalyzed conversion to thiuram disulfides, which oxidize glutathione in a redox cycle without the release of reactive oxygen species, Archives of Biochemistry and Biophysics, 1998, 353, 73-84) dithiocarbamates are cytotoxic: their mechanism of dithiocarbamate toxicity involves the copper-catalyzed conversion of dithiocarbamates to cytotoxic thiuram disulfides.

Katsaros, N., Katsarou, M., Sovilj, S. P., Babic-Samardzija, K., and Mitic, D. M., Biological activity of some cobalt(II) and molybdenum(VI) complexes: in vitro cytotoxicity, Bioinorganic Chemistry and Applications, 2004, 2, 193-207.

Elevated uric acid levels and gout-like symptons

There is some evidence that exposure of industrial workers to high levels of molybdenum trixoide causes increased serum uric acid levels and, in some cases, gout-like symptoms. For copper-molybdenum plant workers (34 out of 37) who complained of arthralgia (pain in the joints) [ USEPA, 1975] serum uric acid levels were increased.

U. S. Environmental Protection Agency (USEPA), 1975, Molybdenum - A toxicological appraisal, EPA-600/1-75-004. Health Effects Research Laboratory, Office of Research and Development, Research Park Triangle, NC.

After an 8-hour exposure of workers in a plant producing molybdenum trioxide to respirable dusts of molybdenum trioxide and other soluble oxides of molybdenum to 9.47 mg/m3 (cf. the OSHA permissible exposure limit 5 mg/m3), mean serum uric acid levels of 25 male workers increased 1.18-fold and mean serum ceruloplasmin (copper transport protein) levels by 1.65-fold compared with unexposed workers; but there was no gout-like syndrome [Walravens et al., 1979]. However, development of gout and multiple sclerosis has been reported in humans exposed to high molybdenum concentrations in food and air [Pitt, 1976].

Walravens, P. A., Moure-Eraso, R., Solomons, C. C., Chappell, W. R.and Bentley, G. 1979.
Pitt, M. A., Agents and Actions, 1976, 6, 758.

In Armenians 10- 15 mg Mo/d (derived from high soil Mo) gave clinical evidence of gout [Kovalskii et al., 1961]. The serum uric acid concentration of 52 adults was 6.2 mg/dL compared with 3.8 mg/dL for controls.The US Environmental Protection Agency (IRIS data-base) used this study to set 140 microg Mo/kg/d as the lowest observable adverse effect level (LOAEL) although "The statistical significance and the methods of ascertainment for this study were unclear' [Barceloux, 1999].

Kovalskii, V.V., Jarovaja, G.A., Shmavonyan, D.M. , Changes in purine metabolism in man and animals in various molybdenum-rich biogeochemical provinces. Zh Obshch Biol, 1961;22:179-191 (Russian translation, IRIS data-base).
Barceloux, D.G., Molybdenum, Journal Of Toxicology-Clinical Toxicology, 1999, 37, 231-237

Metal ions released from orthopaedic implants

Metal ions may be released from orthopaedic implants into the physiological environment [Puleo et al.,1995]. Metal ions from Co-Cr-Mo alloys are toxic to osteogenic cells derived from bone marrow at concentrations near those measured in the fibrous membrane encapsulating orthopaedic implants. To measure the acute toxicity of released metal ions towards osteogenic cells solutions of individual ions and mixtures representing an alloy composition (e.g. Co (66.5%)-Cr(27.5%-Mo(6%), ASTM F75) were added in vitro to cultures of bone marrow stromal cells at concentrations 50 ppb to 50 ppm. The solutions were prepared from atomic absorption standards; the nitrate counterion did not affect cellular response. After 48 h the cultures were examined for effects of cytotoxicity by measuring total cell number, total cell protein and mitochondrial activity. The ranking of ions with respect to toxic effects was: Cr(VI) > Mo(VI) = Fe(III) > Co(II) > Ni(II). Non-toxic were Al(III), Mn(II), Ti(IV), V(V). Among alloys, solutions mimicking Co-Cr-Mo and 316L stainless steels were moderately toxic. After 48 h exposure representative TC50 values (concentrations at which one half of the extent of toxicity was observed) were in ppm and microM:

Cr 0.4, 7.7; Fe 0.7, 13; Mo 0.6, 6.3; Co 2, 34; Ni 3, 51; Co-Cr-Mo 1.5, NA.

Puleo, D.A., Huh, W.W., Acute toxicity of metal ions in cultures of osteogenic cells derived from bone marrow stromal cells, Journal of Applied Biomaterials,1995, 6, 109 - 116.

See also

Pypen, C.M.J.M., Dessein, K., Helsen, J.A., Gomes, M., Leenders, H., DeBruijn, J.D., Comparison of the cytotoxicity of molybdenum as powder and as alloying element in a niobium-molybdenum alloy, Journal Of Materials Science-Materials In Medicine, 1998, 9, 761-765.
Okazaki, Y., Rao, S., Asao, S., Tateishi, T., Effects of metallic concentrations other than Ti, Al and V on cell viability, Materials Transactions Jim, 1998, 39, 1070-1079.

Nickel-based dental alloys may release metal ions to surrounding tissues. Cell culture evaluations can be used to develop a biocompatibility model of the metabolic response to individual ions released from dental alloys. The metabolic and the morphological response of cultured human gingival fibroblasts to salt solutions of ions, including molybdate were measured. Ni2+ ion solutions altered metabolic functions at 3-30 ppm and Cr3+ and Mo6+ at 10 and 100 ppm, Cr6+ and Be2+ causing cellular alterations at 0.04-12 ppm. and were the most toxic [Messer and Lucas, 1999]. Molybdate as ammonium molybdate was the least cytotoxic.

Messer, R.L.W., Lucas, L.C., Evaluations of metabolic activities as biocompatibility tools: a study of individual ions' effects on fibroblasts, Dental Materials, 1999, 15, 1-6.

Alloys used as implants release metal ions to surrounding tissues. Cytotoxic substances attack at the molecular level, and their effects are reflected in the structure of the cells and organelles. The cellular morphology and ultrastructural changes of cultured human gingival fibroblasts obtained from third molar explants to salt solutions of molybdate (and other ions) which may be released from nickel-chromium dental alloys were evaluated. Fibroblasts were exposed to the different ion concentrations for 24 or 72 h. Cellular morphology and ultrastructural features were examined using scanning electron microscopy and transmission electron microscopy. The attack of cytotoxic substances affects the stucture of the cells and these changes are visible in electron microscopy. The cells exposed to ammonium molybdate (100 ppm, 72 h) solution occasionally contained irregularly shaped nuclei. The mitochondria were smaller and slightly fewer in number, which corresponds to intracellular ATP levels similar to untreated cells, indicating a cell is still metabolically active. The decreases in dilated rER correlates to decreases in protein and RNA synthesis. Since myelin figures are formed by hydration of lipidic material, usually through cellular organelle autophagy, the increase in the myelin figures may explain the slight decrease in the number of mitochondria in cells exposed for 72 h and the increase in surface depressions seen in SEM micrographs.

Messer, R.L.W., Bishop, S., Lucas, L.C., Effects of metallic ion toxicity on human gingival fibroblasts morphology, Biomaterials, 1999, 20, 18, 1647-165.

Metal toxicity from orthopaedic implants was investigated in terms of immune system hyper-reactivity to metal implant alloy degradation products. Lymphocyte response to serum protein complexed with metal from implant alloy degradation was investigated in this in vitro study using primary human lymphocytes from healthy volunteers. This in vitro study demonstrated a lymphocyte proliferative response to both Co-Cr- Mo and Ti alloy metalloprotein degradation products. This response was greatest when the metals were complexed with high molecular weight proteins, and with metal-protein complexes formed from Co-Cr-Mo alloy degradation.

Hallab, N.J., Mikecz, K., Vermes, C., Skipor, A., and Jacobs, J. J., Orthopaedic implant related metal toxicity in terms of human lymphocyte reactivity to metal-protein complexes produced from cobalt-base and titanium-base implant alloy degradation, Molecular and Cellular Biochemistry, 2001, 222, 127-136.

Molybdenum in whole blood with particular relevance to patients with total hip and knee arthroplasty

Joint-replacement surgery has revolutionized the treatment of osteoarthritis and is still the most effective therapy. A recent clinical trend reintroducing metal-on-metal bearing surfaces has in turn stimulated a requirement for accurate measurement of the concentrations of relevant metals in both pre- and postoperative patients. Thus, there is a need for cost-effective, multielement methods for trace metal analysis in whole blood to monitor possible increases in wear metal concentrations.

For molybdenum Detection limits in whole blood were 0.06 mug/L.

Base concentrations 0.62 mug/L

Case, C.P., Ellis, L., Turner, J. C., and Fairman, B., Development of a routine method for the determination of trace metals in whole blood by magnetic sector inductively coupled plasma mass spectrometry with particular relevance to patients with total hip and knee arthroplasty, Clinical Chemistry, 2001, 47, 275-280.

Skin lesions from a metal implant containing molybdenum ― alleged histiocytosis associated with molybdenum

A unique case of intralymphatic histiocytosis with granuloma formation associated with orthopaedic metal implants is reported. Asymptomatic reddish-brown nodules were observed on the left knee of a seventy-five year old man; an orthopaedic metal implant had been inserted in the knee for a knee joint disorder. Histopathological examination revealed typical features of mixed cell granuloma with many dilated lymphatics that contained many histiocytes from the upper dermis to subcutaneous fat tissue. Biopsy specimens were analysed qualitatively by energy-dispersive X-ray spectroscopy and were positive for molybdenum, one of the constituents of the metal implant. It is suggested that the synovial fluid containing molybdenum had drained into the skin lesion from the synovial cavity of the left knee. The lesions disappeared following drainage.

[Intralymphatic: situated within or introduced into a lymphatic vessel

Histiocytosis: an abnormal increase in the number of certain immune cells, called

Histiocyte: A macrophage (cell which ingests particulate materials) found within the tissues.

Granuloma: a localised accumulation of macrophages around the site of some continuing stimulus, e.g. injury, inflammation or infection, having their cell membranes fused together so as to form multinucleated giant cells.]

COMMENT. The case of intralymphatic histiocytosis associated with an orthopaedic metal implant reported in this paper is unique. Any significance to be attached to molybdenum in the biopsy specimens is not clear and is not discussed. There is, of course, no control.

Watanabe, T., Yamada, N., Yoshida, Y., and Yamamoto, O., Intralymphatic histiocytosis with granuloma formation associated with orthopaedic metal implants, British Journal of Dermatology, 2008, 158, 402-404.

Molybdate toxicity to human T-cells

The effect of molybdenum and other metal ions (from aluminium, chromium, cobalt, copper, iron, nickel, niobium, vanadium, and zirconium) on DNA damage, apoptosis, necrosis, and proliferation responses of a human T-helper lymphocyte (Jurkat) cell line were evaluated. The interest is in the long-term physiological effects on the cells of the adaptive immune system, T-helper lymphocyte.cells, of component degradation of metal devices in medical applications: total joint arthroplasties, stents and pacemakers. The metal ions were applied as aqueous chloride solutions at concentrations 0.05 to 5.0 molybdenum. The DNA damage, apoptosis, necrosis, and proliferation responses of a human T-helper lymphocyte (Jurkat) cell line were evaluated. The paper should be consulted for details of the techniques and data analysis. For molybdenum the following observations were reported:

  • Of all the metals molybdenum (and niobium) induced the least DNA damage with no damage up to the highest dose (5 mM).
  • Molybdenum (and zirconium, niobium and copper) was “moderately” apoptotic [apoptosis, programmed cell death, resulting from irreversible cell damage by the metal ions] inducing more than 50% caspase-9 positive cells at 0.5 mM or higher.
  • Molybdenum (and aluminium, chromium and iron) did not induce any “significant” viability reduction in Jurkat T cells at any concentration tested.
  • Molybdenum (and chromium) had a “relatively small effect” on Jurkat T lymphocyte viability (more than 80% viability at the highest dose).
  • Molybdenum (and beryllium and nickel) only “moderately” inhibited cell proliferation (metabolism) of Jurkat T lymphocytes at 0.5 mM and did not reduce proliferation at <1 mM.

Caicedo, M., Jacobs, J. J., Reddy, A., and Hallab, N. J., Analysis of metal ion-induced DNA damage, apoptosis, and necrosis in human (Jurkat) T-cells demonstrates Ni2+, and V3+ are more toxic than other metals: Al3+, Be2+, Co2+, Cr3+, Cu2+, Fe3+, Mo5+, Nb5+, Zr2+, Journal of Biomedical Materials Research Part A, 2008, 86A, 905-913.

Implant debris – Metal-induced lymphocyte reactivity

Aseptic osteolysis [dissolution of bone] has been associated with excessive immune reactivity to particulate implant debris; however, innate and adaptive immune mechanisms that underlie implant debris reactivity remain incompletely understood.

Although particulate debris has been implicated as the major type of implant debris mediating macrophage-induced osteolysis, the degree to which metal ions affect a proinflammatory response (if at all) remains unknown.

The hypothesis to be tested was that both soluble and particulate metal implant debris will induce proinflammatory responses in human monocytes [white blood cells which ingest foreign particles, e.g. bacteria and tissue debris] resulting in production of cytokine [protein molecules involved in immune response] and elevated expression of T cell costimulatory molecules, facilitating adaptive immune responses.

The response to Co-Cr-Mo alloy particles and soluble cobalt, chromium, molybdenum, and nickel ions of a human monocyte cell line (THP-1), isolated primary human monocytes and PBMCs was determined. Soluble cobalt, nickel, and molybdenum induced monocyte up-regulation of T cell costimulatory molecules (CD80, CD86, ICAM-1) in human monocytes/macrophages.

Cobalt, molybdenum ions, and Co-Cr-Mo alloy particles similarly induced elevated secretion of IL-1 beta, TNF alpha, and IL-6.

Antibody blockade of CD80 and CD86, crucial secondary molecules for adaptive responses, abrogated lymphocyte reactivity to metal challenge in metal reactive subjects.

The addition of IL-1 receptor antagonist (IL-1ra), (which indirectly blocks pro-IL-1 beta and thus IL-1 beta release), significantly reduced lymphocyte reactivity in metal-reactive subjects.

Both soluble and particulate metal implant debris induce monocyte/macrophage proinflammatory responses that are metal and individual specific. This suggests metal-induced up-regulation of costimulatory molecules and proinflammatory cytokine production is necessary to induce lymphocyte activation/proliferation to metal implant debris.

Caicedo, M. S., Pennekamp, P. H., McAllister, K., Jacobs, J. J., and Hallab, N. J., Soluble ions more than particulate cobalt-alloy implant debris induce monocyte costimulatory molecule expression and release of proinflammatory cytokines critical to metal-induced lymphocyte reactivity, Journal of Biomedical Materials Research Part A, 2010, 93A, 1312-1321.

Therapeutic Uses of Molybdenum

Molybdenum is an essential trace element and is a component of vitamin and mineral supplements. Some therapeutic uses of molybdenum compounds are described in this section.

Treatment of anaemia

Magnesium molybdate in daily doses of 0.06-0.20 g Mo has been used in the treatment of various conditions including anaemia and as a general tonic for restoring appetite after convalescence [Vignoli and Defretin, 1963].
Vignoli L.and Defretin, J. P., Biologie medicale, 1963, 52, 319.
A sustained-release preparation of a molybdenised iron(II) sulfate is capable of promptly correcting iron deficiency anaemia and is prescribed for this purpose [Mouratoff and Batterman, 1961; Stevenson, 1962; Rudolph et al., 1963].
Mouratoff, G. L. and Batterman, R. C., J. New Drugs, 1961,1,157.
Stevenson, T. D., Current Therapeutic Research, 1962, 4, 107.
Rudolph, I., Ongchangco, M. N. and Fink, H., Current Therapeutic Research, 1963, 5, 517.

Prevention of dental caries

It is well known that fluoride is effective against the development of dental caries in experimental animals and in human beings. There is evidence that trace elements, particularly molybdenum, in the water supply and in food, enhance the cariostatic effect of fluoride [Schutte, 1964]. For example, children fed on vegetables from the molybdenum-rich Napier area of New Zealand had fewer caries than children from other areas. Similar epidemiological studies in Europe and the United States have confirmed the cariostatic effect of molybdenum [Lossee and Bibby, 1970; Hadjimarkos, 1966; Anderson, 1969; Jenkins, 1967; Lossee and Adkins, 1971].

Schutte, K. H., The Biology of the Trace Elements, Crosby Lockwood and Son Ltd., London, 1964, 92.
Lossee, F. L. and Bibby, B. G., New York State Dental Journal, 1970, 36, 15.
Hadjimarkos, D. M., Anderson, R. J., Caries Res., 1969, 3, 75.
Arch. Environ. Health, 1966, 13, 102.
Jenkins, G., British Dental Journal, 1967, 435, 500, 545.
Lossee, F. L. and Adkins, B. L., Geol. Soc. Amer., Mem., 1971, 123, 203.

The incidence of dental caries is lower in parts of Hungary than would be expected from the fluoride content of the water supply. On investigation it was found that the molybdenum content of the drinking water was high. Further studies from New Zealand, from the cities of Hastings and Napier, showed that the incidence of caries in Napier was significantly less than in Hastings, although both towns had the same water supply. However, the inhabitants of Napier ate vegetables grown in soil that had been under the sea until raised by an earthquake 30 years ago; the concentration of molybdenum was much higher in this soil than in that around Hastings. The molybdenum content of the teeth of boys living in Napier was higher than that of boys in Hastings, although the hair content of molybdenum in boys from both cities was the same. Another piece of evidence suggesting that deficiency of molybdenum plays a part in dental caries is that in Somerset UK the incidence of caries is high in children from areas where the cattle suffer from molybdenum deficiency.

Many workers have given molybdenum to animals and confirmed its anti-cariogenic properties, although in some cases the dose of molybdenum was high. It is not yet established what is the effective anti-cariogenic dose of molybdenum, at what stage in tooth formation it acts, or whether there is any relation between fluoride and molybdenum. Molybdenum has been shown to reduce the solubility of teeth in acid and also to reduce the acid output by the salivary glands. It is more likely that molybdenum acts by affecting the morphology of teeth than by other mechanisms. There is an additive effect between the benefits of fluoride and molybdenum, though fluoride is undoubtedly the more important. Molybdenum increases the absorption of fluoride from the stomach.

The route by which molybdenum reached individuals living in areas of molybdenum-rich soils was through locally produced and consumed vegetables and especially milk [Anderson, 1969]. Water supplies do not make an important contribution to the daily intake of molybdenum [Hadjimarkos, 1966]. The effect of molybdenum and other trace elements on the development of dental caries in experimental animals has been studied [Navia, 1970; Bertrand et al., 1972; Helsby, 1973]. Molybdenum and also vanadium and strontium were mildly cariostatic. There are indications that ammonium molybdate, (NH4)2MoO4, is cariostatic but that ammonium heptamolybdate, (NH4)6Mo7O24.4H2O, is not [Jenkins, 1967]. The enamel of rat teeth formed in the presence of molybdenum and fluoride has been examined by electron microscopy [Kruger, 1969]. Both elements influence mineralisation. The cariostatic effect of molybdenum is well established and there is need for more research, especially on the mechanism of its action, the level required, and the method of administration.

Hadjimarkos, 1966; Anderson, 1969; Jenkins, 1967; Lossee and Adkins, 1971].
Navia, J. M., Advan. Chem. Ser., 1970, 94, 123.
Bertrand, G., Blanquet, P. and Laparra, J. C. R. Soc. Biol., 1972, 166, 353.
Helsby, C. A., Caries Res., 1973, 7, 332.
Jenkins, G., British Dental Journal, 1967, 435, 500, 545.
Kruger, B. J., J. Dent. Res., 1969, 48, 1303.

Effect of molybdenum on the immunological reactivity of organisms

The addition of molybdenum as an aqueous solution of ammonium molybdate in amounts of 50-250 mg/kg to the diet of rabbits daily for up to 12 months increased the immunological reaction towards Bact. proteus OX19 culture. The optimum dose was 250 mg/kg when the amount of antibodies and phagocytes was two to three times higher than in control animals [Devyatka et al., 1971].

Devyatka, D. G., Val'chuk, N. K., Voronina, T. Z. and Bukhovets, V. J., Gig. Sanit., 1971, 36, 104.

Molybdenum and cancer

For a review see

Metal passivity as mechanism of metal carcinogenesis: Chromium, nickel, iron, copper, cobalt, platinum, molybdenum, CORNELIA RICHARDSON-BOEDLER Toxicological & Environmental Chemistry, Jan–Mar 2007; 89(1): 15–70.

There are indications of a relationship between molybdenum deficiency and the development of various tumours. The incidence of oesophageal cancer in areas of South Africa varies depending on location [Davies, 1975; Rose, 1968; Burrell et al., 1966]. The gardens of a group of Bantu women who died of cancer were less fertile and less productive than those of tumour-free women. Severe signs of molybdenum deficiency were noted in plants grown in gardens of the cancer sufferers. It is suggested that the molybdenum deficiency resulted in the plants being more prone to attack by fungi, e.g. Aspergillus flavus, which has been implicated as a cause of liver cancer in animals. The distribution of molybdenum in mouse liver and Sarcoma 180 was determined following the intraperitoneal injection daily for 6 d of various molybdenum compounds [Caruthers and Regelson, 1963]. With Na4SiMol2O40, MoCl5, and MoBr2 there was an accumulation of molybdenum in the liver and the tumour but with (NH4)6Mo7O24.4H2O and Mo3(H2C2O4).2H2O there was no such accumulation. The copper and zinc contents of the liver and the tumour were not affected by any of the molybdenum compounds nor was the growth rate of the tumour. It is possibly relevant that the concentration of xanthine oxidase is relatively low in various tumours and that tumour growth in mice was decreased by treatment with xanthine oxidase concentrates [Bray, 1963].

Davies, I. J. T., Intake (British Medical Journal. Advertiser's Supplement), 1975, 39, 4.
Rose, E. F., Cancer Research, 1968, 28, 2390.
Burrell, R. J. W., Roach, W. A. and Shadwell, A., J. Nat. Cancer Inst., 1966, 36, 201, 211.
Caruthers C.and Regelson, W.,Oncologia, 1963, 16, 101.
Bray, R. C., in The Enzymes, ed. Boyer, P. D., Hardy, L. and Myrback, K., Academic Press, New York, 2nd Edn., 1963, 7, 533.

Two randomised nutrition intervention trials were conducted in Linxian, an area of north central China with some of the world's highest rates of oesophageal and stomach cancer and a population with a chronically low intake of several nutrients. to assess the effects in nearly 30 000 participants of daily supplementation with: retinol and zinc; riboflavin and niacin; vitamin C and molybdenum; and beta-carotene, alpha-tocopherol, and selenium. The second trial provided daily multiple vitamin-mineral supplementation; or placebo in 3318 persons with oesophageal dysplasia, a precursor to oesophageal cancer. After supplements were given for 5.25 y in the general population trial, small but significant reductions in total relative risk [(RR) = 0.91] and cancer (RR = 0.87) mortality were observed in subjects receiving beta-carotene, alpha-tocopherol, and selenium but not the other nutrients. The largest reductions were for cerebrovascular disease mortality, but the effects differed by sex: a significant reduction was observed in men (RR = 0.45) but not women (RR = 0.90).Restoring adequate intake of certain nutrients may help to lower the risk of cancer and other diseases in this high-risk population [Blot et al., 1995].

Blot, W.J., Li, J.Y., Taylor, P.R., Guo, W.D., Dawsey, S.M., Li, B.,. The Linxian Trials - Mortality-Rates By Vitamin-Mineral Intervention Group, American Journal Of Clinical Nutrition,1995, 62, S1424-S1426.

Xanthine dehydrogenase (EC is a molybdenum iron-sulfur, flavin hydroxylase involved in purine catabolism. Xanthine dehydrogenase-induces activation of bioreductive agents including chemotherapeutic agents requiring bioreductive activation for their antineoplastic activities. Xanthine dehydrogenase is potentially important as an enzyme targeted in chemotherapeutic regimens is discussed [Pritsos et al., 1994].

Pritsos, C.A., Gustafson, D.l., Xanthine Dehydrogenase And Its Role In Cancer-Chemotherapy, Oncology Research, 1994, 6, 477-481.

The antitumor active molybdocene dichloride Cp2MoCl2 formed two stable adducts at pD 6 which were tentatively assigned as a Cp2Mo-glutathione chelate involving coordination of the cysteine thiol and glycine carboxylate to the molybdenum centre, and a thiol centred 1:2 Cp2Mo-glutathione complex. The implications for the mechanism of antitumor action of the metallocene dihalides are discussed.

Mokdsi, G. and Harding, M. M., A H-1 NMR study of the interaction of antitumor metallocenes with glutathione, Journal of Inorganic Biochemistry, 2001, 86, 611-616.

Interest in the aqueous, bio-organometallic chemistry of metallocene dihalides has stemmed from the potent antitumor properties of titanocene dichloride, including results from human clinical trials. Key results on the biological chemistry of molybdocene dichloride are reviewed. Under physiological conditions the positively charged monoaquated species Cp2Mo(OH)(OH2)+, in equilibrium with the dipositively charged dimer Cp2Mo(mu-OH)2MoCp2, is present.Studies of the coordination chemistry of Cp2MoCl2 with nucleobases, nucleotides, single-stranded and double-stranded oligonucleotides, and calf-thymus DNA have shown that, while simultaneous phosphate(O) and heterocyclic(N) adducts are formed with nucleotides, negligible interaction with DNA occurs under physiological conditions. Cp2MoCl2 forms strong, non-labile complexes with deprotonated thiols in amino acids. Molybdocene dichloride is able to catalyse the hydrolysis of activated phosphate esters under physiological conditions, but hydrolysis of unactivated phosphodiesters is only significant at pH 4. Limited antitumor activity results, inhibition studies with protein kinase C and topoisomerase II, structure-activity and cell-uptake studies have provided some insight into possible mechanisms of antitumor action.

Waern, J.B. and Harding, M. M., Bioorganometallic chemistry of molybdocene dichloride, Journal of Organometallic Chemistry, 2004, 689, 4655-4668.

The compounds molybdenocene dichloride (Cp2MoCl2) and [Cp2Mo(L)(n)]Cl2 (n = 1, L = 6-mercaptopurine, 6- mercaptopurineribose, 2-amine-6-mercaptopurine and 2-amine-6- mercaptopurineribose and n = 2, L = D-penicillamine) have antitumour properties. Their complexes with calfthymus DNA have been investigated by cyclic voltammetry. (Cp2MoCl2) and [Cp2Mo(L)(n)]Cl2 (n = 1, L = 2-amine-6- mercaptopurine and 2-amine-6-mercaptopurineribose and n = 2, L = D-penicillamine) complexes showed weak DNA bindings (3.2- 10.1%) while the complexes containing the ligands 6- mercaptopurine and 6-mercaptopurineribose showed negligible interactions.

Rodriguez, M.I., Chavez-Gil, T., Colon, Y., Diaz, N., and Melendez, E., Molybdenocene-DNA interaction studies using electrochemical analysis, Journal of Electroanalytical Chemistry, 2005, 576, 315-322.

Mo and cancer molybdenocene

In the range 4 <=, pD <=, 9 by NMR spectroscopy the ribonucleosides and ribonucleoside monophosphates uridine, adenosine, cytidine, guanosine, 5'-UMP, 5'-AMP, 5'-CMP and 5'-GMP bind Cp2Mo2+ exclusively through the ribose moiety giving rise to the chelate complexes [Cp2Mo(urd-O2',O3')], [Cp2Mo(ade-O2',O3')], [Cp2Mo(cyd-O2',O3')], and [Cp2Mo(gua-O2',O3')]. The ribonucleotides form three types of complex with Cp2Mo2+ in neutral solution, namely N,PO-macrochelates, PO,O3'-coordinated species as well as O2',O3'-chelates, while at pD 9 only sugar coordination is observed.

Erxleben, A. and Yovkova, L., Reaction behavior of molybdocene dichloride towards ribonucleosides and ribonucleoside monophosphates: Rare example of sugar coordination, Inorganica Chimica Acta, 2006, 359, 2350-2360.
Waern, J.B., Harris, H. H., Lai, B., Cai, Z. H., Harding, M. M., and Dillon, C. T., Intracellular mapping of the distribution of metals derived from the antitumor metallocenes, Journal of Biological Inorganic Chemistry, 2005, 10, 443-452.

Molybdocene is cytotoxic

In V79 Chinese hamster lung cells Cp2MoCl2 produced significant genotoxic damage: 0.2 micronuclei/1000 binucleated cells were induced per mu M of Cp2MoCl2. Distinct morphological alterations of the nuclei, condensation of chromatin, and a high incidence of polynucleated cells were observed. Implications for the mechanism of antitumor action of molybdocene dichloride are discussed. (c)

Campbell, K. S., Foster, A. J., Dillon, C. T., and Harding, M. M., Genotoxicity and transmission electron microscopy studies of molybdocene dichloride, Journal of Inorganic Biochemistry, 2006, 100, 1194-1198.

Anti-cancer activity of molybdophosphate: heteropoly Mo

The review includes a useful account of the biochemical activity of molybdenum heteropoly compounds, specifically 12-molybdophosphoric acid, and applications as biomedical agents: antitumoral, anticoagulant, antibacterial, antiviral activity. The antitumour activity of molybdophosphoric acid in in vitro tests on human cervix carcinoma cells was low and less than the activity of tungstophosphoric acid. Molybdophosphoric acid did not damage red blood cells. Molybdophosphoric caused a slight increase of the coagulation time of human blood plasma (49 s compared with 40 s) but less than tungstophosphoric acid (100 s). The polyoxometallates did not exhibit antibacterial activity or antiviral activity on plant viruses.

Mioc, U. B., Todorovic, M. R., Davidovic, A., Colomban, P., and Holclajtner-Antunovic, I., Heteropoly compounds - From proton conductors to biomedical agents, Solid State Ionics, 2005, 176, 3005-3017.


The polyoxomolybdate hexabis(isopropylammonium) heptamolybdate trihydrate, [NH3Pri]6[Mo7O24].3H2O (PM-8) suppressed the growth of Co-4 human colon cancer, MX-I human breast cancer and OAT human lung cancer xenografted in nude mice. In an MTS assay DNA ladder formation and detection of apoptotic bodies in nuclei showed that antitumor activity of PM-8 in MKN45 cells was due to apoptosis [programmed cell death]. PM-8 shows promise as a novel anti-cancer agent.

Mitsui, S., Ogata, A., Yanagie, H., Kasano, H., Hisa, T., Yamase, T., and Eriguchi, M., Antitumor activity of polyoxomolybdate, [NH3Pri]6[Mo7O24].3H2O, against, human gastric cancer model, Biomedicine & Pharmacotherapy, 2006, 60, 353-358.

See also

Oda, M., Inoue, M., Hino, K., Nakamura, Y., and Yamase, T., Enhancement effect of polyoxometalates on NGF-induced neurite-outgrowth of PC12 cells, Biological & Pharmaceutical Bulletin, 2007, 30, 787-790.

2,5-dihydroxybenzoate molybdenum(VI) complex

2,5-dihydroxybenzoate molybdenum(VI) complex may provide a valuable tool in cancer chemotherapy

Thomadaki, H., Karaliota, A., Litos, C., and Scorilas, A., Enhanced antileukemic activity of the novel complex 2,5-dihydroxybenzoate molybdenum(VI) against 2,5-dihydroxybenzoate, polyoxometalate of Mo(VI), and tetraphenylphosphonium in the human HL-60 and K562 leukemic cell lines, Journal of Medicinal Chemistry, 2007, 50, 1316-1321.

Diabetes - anti-diabetic properties of molybdenum compounds

Reactivity of potential anti-diabetic molybdenum(VI) complexes in biological media

A study of molybdenum (VI) compounds as potential anti-diabetic agents is reported. Oxo anions ([MO4]2−or [MO4]3− where M = V, Cr, Mo or W) have anti-diabetic properties. It is considered that oxoanions inhibit the tyrosine phosphatase enzyme by replacing phosphate in the active centers of the enzyme thereby enhancing insulin signalling.

In the body oxoanions are not absorbed via the intestine. Therefore the idea is to supply molybdenum as an uncharged hydrophobic complex capable of being absorbed in the intestine and converted in the blood stream to molybdate. The complexes should be stable under gastric and intestinal digestion conditions. The study also, incidentally, provides information on the stability and speciation of molybdenum compounds and molybdate under digestive conditions and in the blood.

The compounds studied were sodium molybdate and complexes [MoO2L2] where L is a bidentate ligand:

A: sodium molybdate, Na2[MoO4]

B: [MoO2(acac)2] (B; acacH = acetylacetone = 2,4-pentanedione) having molybdenum (VI) in distorted octahedral coordination by six oxygens

C: [MoO2(cyset)2] (C;cysetH = L-cysteine ethyl ester) having molybdenum (VI) in distorted octahedral coordination by two oxygens, two nitrogens and two sulfurs

D: [MoO2(dedtc)2](D; dedtcH = N,N-diethyldithiocarbamic acid). having molybdenum (VI) in distorted octahedral coordination by two oxygens and four sulfurs

Each complex was applied mixed with chemically inert boron nitride to simulate an oral pharmaceutical preparation. They were subjected under physiological conditions (37 °C) to: artificial gastric and intestinal digestion with semi-synthetic meal; simulated gastric juice (pH = 1.2); simulated intestinal fluid (pH = 7.5); cell culture medium (DMEM) with 10% fetal calf serum; and horse serum, heat-inactivated. Sodium molybdate was added to intact human blood then plasma separated and intact human blood then red blood cells separated. Molybdenum concentrations were 1.0 mM (100 ppm).

The compounds and their speciation were studied by Mo K-edge XANES (X-ray absorption near-edge structure) spectroscopy. The XANES spectra enable one to distinguish beween tetrahedral molybdenum(VI) (as in the molybdate anion) and octahedral molybdenum(VI) (as in the complexes) and to deduce the ligand envirionment of the molybdenum atom (2O + 4O or 2N and 2S or 4S) and hence the speciation of molybdenum(VI) under the conditions employed. The [MoO2L2] complexes decomposed under simulated gastric and intestinal digestion conditions (3 h at 37 °C), and in blood plasma and cell culture medium (24 h at 37 °C). The dithiocarbamato complex (D) was less reactive than the other complexes, decomposing in the meal but not in the gastric and intestinal liquids. The reaction products of [MoO4]2- and [MoO2L2] with the biological fluids were modelled as mixtures of tetrahedral and octahedral Mo(VI) oxo-species (i.e. having molybdenum ligated only with oxygen atoms) in various ratios depending on the nature of the medium. Red blood cells took up Mo(VI) predominantly as the [MoO4]2- ion. The octahedral oxo-Mo(VI) species were formed in more acidic media ([H+] = 2–6 M) as the monomeric [MoO2(OH2)4]2+ ion or as polynuclear molybdophosphates, e.g. [Mo5O15(PO3OR)2]2−, where R is the nucleoside residue (known to be formed in solutions of molybdate and nucleosides at pH = 4–5).

Levina, A., McLeod, A., Seuring, J., and Lay, P. A., Reactivity of potential anti-diabetic molybdenum(VI) complexes in biological media: A XANES spectroscopic study, Journal of Inorganic Biochemistry, 2007, 101, 1586-1593

Lowering blood glucose and free fatty acid levels

Both Na2MoO4 (used as a control) and cis-MoO2L22 L= maltol (3-hydroxy-2-methyl-4-pyrone) were effective in lowering blood glucose and free fatty acid levels. Diabetic rats treated with molybdate showed significant improvements in postischemic cardiac function.

Lord, S.J., Epstein, N.A., Paddock, R.L., Vogels, C.M., Hennigar, T.L., Zaworotko, M.J., Taylor, N.J., Driedzic, W.R., Broderick, T.L., Westcott, S.A., Synthesis, characterization, and biological relevance of hydroxypyrone and hydroxypyridinone complexes of molybdenum, Canadian Journal Of Chemistry-Revue Canadienne De Chimie, 1999, 77, 7, 1249-1261.

Tetrathiomolybdate and Wilson’s disease

Ammonium tetrathiomolybdate treats chronic Cu poisoning in sheep and is recommended for Wilson's disease in humans (congenital inability to excrete copper resulting in its accumulation) [Haywood et al., 1998]. In the tetrathiomolybdate-treated sheep Mo accumulated in brain, liver, kidney, heart, skeletal muscle, pituitary, adrenals, testes and ovaries and was retained after cessation of treatment, except in liver, kidney and skeletal muscle. Cu increased and was retained in the cerebellum and medulla oblongata in the tetrathiomolybdate-treated high-Cu Cambridge groups. Brain Cu and Mo concentrations showed a strongly positive correlation in the high-Cu Ronaldsay group 7 months after tetrathiomolybdate treatment. Tetrathiomolybdate is not all excreted; Mo is widely distributed and retained in many organs including brain and pituitary. Tetrathiomolybdate may redistribute some displaced excess liver Cu to the brain.

Haywood, S, Dincer, Z, Holding, J, Parry, NM, Metal (molybdenum, copper) accumulation and retention in brain, pituitary and other organs of ammonium tetrathiomolybdate-treated sheep, British Journal Of Nutrition, 1998, 79, 329-331.

The uptake of tetrathiomolybdate by the liver and the removal of copper accumulating in the liver in a form bound to metallothionein by tetrathiomolybdate were studied in Long-Evans cinnamon (LEC) rats, an animal model of Wilson’s disease, in order to develop better treatments for the disease and Cu toxicity [Ogra and Suzuki, 1998]. When the dose of tetrathiomolybdate is low, tetrathiomolybdate forms a complex with Cu that can be effluxed into the bloodstream, and then binds selectively to albumin. When the dose is high, tetrathiomolybdate forms an insoluble complex, that is precipitated in the liver. Tetrathiomolybdate taken up by a cell is immobilized in the cell through the dose-dependent formation of a complex containing Cu, Mo and sulfur, which causes further uptake of tetrathiomolybdate. Tetrathiomolybdate does not remove Cu from ceruloplasmin. Tetrathiomolybdate targets a cell accumulating excess Cu as Cu- metallothionein, and removes Cu selectively without interacting with Cu in Cu-enzymes. Tetrathiomolybdate is taken up by the liver depending on the amount of Cu accumulating in the form of metallothionein, and then Cu is effluxed together with Mo in the form of Cu/tetrathiomolybdate complex into the bloodstream.

Ogra, Y., Suzuki, K.T., Targeting of tetrathiomolybdate on the copper accumulating in the liver of LEC rats, Journal Of Inorganic Biochemistry, 1998, 70, 49-55.

Tetrathiomolybdate removes copper accumulating in the form bound tometallothionein in the livers of Wilson’s disease patients and Long-Evans rats with a cinnamon-like coat color (LEC rats). Copper in Cu-containing enzymes such as Cu,Zn-superoxide dismutase in liver and ceruloplasmin in plasma was decreased by thiomolybdate; the Cu is in the plasma as a Cu/thiomolybdate/albumin complex. The decreased amounts of Cu in superoxide dismutase and ceruloplasmin were explained by the sequestration of Cu from their chaperones by thiomolybdates rather than the direct removal of Cu from the enzymes. Hepatotoxicity was observed occasionally in the clinical application of tetrathiomolybdate. The activity of glutamic-pyruvic transaminase in serum increased when Wistar rats were treated with sulfide produced through hydrolytic degradation of tetrathiomolybdate and dithiomolybdate. Hydrolytic degradation was enhanced under acidic conditions. Dithiomolybdate DTM is not appropriate as a therapeutic agent for Wilson’s disease due to its easy hydrolysis and production of sulfide.

Ogra,Y., Komada,Y., Suzuki, K.T., Comparative mechanism and toxicity of tetra- and dithiomolybdates in the removal of copper, Journal Of Inorganic Biochemistry, 1999,75, 199-204.

The chemistry, biology and therapeutic uses of the thiometallate anions of molybdenum(VI) have been reviewed.

Laurie, S.H., Thiomolybdates - Simple but very versatile reagents, European Journal of Inorganic Chemistry, 2000, 2443-2450.

Metallothionein-bound copper in the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson's disease, was removed with ammonium tetrathiomolybdate injected intravenously. 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. In Wistar rats (normal Cu metabolism) most of the Mo was excreted into the urine. The Cu excreted into both the bile and plasma was accompanied by an equimolar amount of Mo.

Komatsu, Y., Sadakata, I., Ogra, Y., and Suzuki, K. T., Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats, Chemico-Biological Interactions, 2000, 124, 217-231.

Wilson's disease is caused by the excessive accumulation of Cu. It is caused by the mutation of genes encoding Cu-binding ATPase for the efflux of Cu. Toxicological studies have elucidated the underlying mechanisms of the occurrence of acute hepatitis caused by the accumulation of Cu accumulating in the liver of an animal model for Wilson disease, LEC rats. Copper forms a stable ternary complex with molybdenum and sulfur under reductive conditions in the body. Tetrathiomolybdate has been applied to remove Cu from the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats). An appropriate protocol for the chelation therapy is proposed together with the mechanisms underlying the occurrence of side-effects

Suzuki, K.T. and Ogura, Y., Biological regulation of copper and selective removal of copper: Therapy for Wilson disease and its molecular mechanism, Yakugaku Zasshi-Journal of the Pharmaceutical Society of Japan, 2000, 120, 899-908.
George, G.N., Pickering, I. J., Harris, H. H., Gailer, J., Klein, D., Lichtmannegger, J., and Summer, K. H., Tetrathiomolybdate causes formation of hepatic copper- molybdenum clusters in an animal model of Wilson's disease, Journal of the American Chemical Society, 2003, 125, 1704-1705.

Ammonium tetrathiomolybdate in treating copper poisoning and Wilson’s disease

Ammonium tetrathiomolybdate (TTM) is an effective treatment for chronic copper poisoning in sheep; it has also been proposed for the treatment of Wilson’s disease in humans. The long-term effects of TTM on five copper-poisoned sheep are reported. The copper-poisoned sheep, after apparently successful treatment with TTM, became infertile and progressively unthrifty and eventually died 2-3 years after treatment. In the TTM treated sheep there was minimal liver damage and no thyroid changes. There was no evidence of neuronal damage in any region of the brain. There were regressive pathological changes of the testes or ovaries, the adrenal glands and the pituitaries associated with the elevated levels of molybdenum. Excess of molybdenum was found in the pituitaries, the adrenals and the brains of affected sheep. Evidently molybdenum introduced systemically as TTM was retained within the brain, pituitary and adrenal glands and so was associated with a toxic endocrinopathy. It is postulated that molybdenum administered as thiomolybdate adversely affects the hypothalamo-adrenohypophyseal system by interfering with trophic hormone release, leading to the cessation of reproductive activity and ultimately the failure of intermediary metabolism. It was proposed that thiomolybdate, directly or indirectly, inhibits the enzyme peptidylglycine á-amidating mono-oxygenase (PAM), an enzyme crucial for the bioactivation of many peptide hormones, including neuropeptides, and a key enzyme in the correct functioning of the neuroendocrine system. PAM is a copper-dependent enzyme. It is found in high concentration in the hypothalamus. Tetrathiomolybdate, in binding to copper in the pituitary or hypothalamus, would make copper unavailable for PAM and thereby inhibit its activity.

Haywood, S., Dincer, Z., Jasani, B., and Loughran, M. J., Molybdenum-associated pituitary endocrinopathy in sheep treated with ammonium tetrathiomolybdate, Journal of Comparative Pathology, 2004, 130, 21-31.

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