Molybdenum in Human Health

Molybdenum levels in humans

In considering physiological effects of molybdenum deficiency and excess, and possible toxic effects of molybdenum, it is important to know whether it accumulates in the body as a result of repeated exposure to low doses. The evidence obtained with experimental animals is that molybdenum is absorbed and excreted rapidly but the rate of excretion is less than the rate of absorption so there is some accumulation of molybdenum in the body (especially bones) and the amount stored increases with dose.

Trace Elements and Oral Health: A Systematic Review,

Background: The role of trace elements in the maintenance of oral health is a very debatable issue. With respect to dental caries, there are certain trace elements that may aid in the progression of dental caries, whereas there are some trace elements which may stop the development of dental caries. Irrespective of their role in oral health, these trace elements form an indispensable part of human growth and nutrition. They are required for performing certain essential physiologic functions in the human body. This systematic review was conducted with the aim to assess the role of trace elements on oral health particularly dental caries.

Materials and Methods: Appropriate guidelines determined for systematic reviews were followed. The time frame selected for the current systematic review was from the year 1952-2014. The studies were selected from various electronic databases on the basis of their title, study design, keywords, and their abstracts. A total of 128 citations were identified following initial searching, and after screening, and quality appraisal 28 studies were included.

Results: A reduction in the incidence of new carious lesions was associated with elements such as fluorides, molybdenum, strontium, lithium, and vanadium. On the other hand, caries-promoting agents were found to be elements such as selenium, cadmium, lead, copper, and others.

Conclusion: Trace elements are vital for the human body to maintain normal yet complex physiological functions related to body's growth and development. The trace elements important for good oral health are molybdenum, fluoride, vanadium, strontium, and lithium.

Pathak, M. U., Shetty, V., and Kalra, D.,Trace Elements and Oral Health: A Systematic Review,

 

Absorption and excretion of molybdenum

Effect of Pregnancy on the Levels of Urinary Metals for Females Aged 17-39 Years Old: Data From National Health and Nutrition Examination Survey 2003-2010

Data from National Health and Nutrition Examination survey for the years 2003-2010 were used (n=1565) to evaluate the effect of age, parity, body mass index (BMI), race/ethnicity, pregnancy, iron (Fe) storage status, smoking status, and fish/shellfish consumption on the levels of urine barium (Ba), cadmium (Cd), cesium (Cs), cobalt (Co), molybdenum (Mo), lead (Pb), antimony (Sb), thallium (TI), tungsten (W), uranium (U), and mercury (Hg) for females aged 1739 yr old. Regression analysis was used to fit models for each of the 11 metals.
For Cd, Cs, TI, and Hg, age was positively associated with levels of these metals. Body mass index was negatively associated with levels of Cs, Co, and TI. Levels of Co, Mo, and W increased over the period 20032010. Over the same period, levels of Pb, Sb, and Hg declined. Non-Hispanic blacks showed lower levels of almost all metals compared to either Mexican American or other unclassified race/ethnicities. Non-Hispanic whites displayed higher levels than non-Hispanic blacks for 9 of 11 metals. Smokers displayed significantly higher levels of Pb, Sb, W, and U than nonsmokers but significantly lower levels of Cd and Mo than nonsmokers.
Pregnancy was found to be associated with higher levels of Ba, Cs, Co, Mo, Pb, W, and Hg compared to nonpregnant females. Levels of Mo, Cs, and Cd declined significantly during the pregnancy period but levels of Co rose during the same period.

Jain, R. B., Effect of Pregnancy on the Levels of Urinary Metals for Females Aged 17-39 Years Old: Data From National Health and Nutrition Examination Survey 2003-2010, Journal of Toxicology and Environmental Health-Part A-Current Issues, 2013, 76, 86-97.

Molybdate diet polyphenol interaction

Trace elements are inorganic constituents of the human body present in concentrations less than 50mg/kg body weight. An exception is iron that is found in slightly higher amounts, 60mg/kg body weight, but it is classified within this category due to its physiological roles. Requirements of trace elements can vary according to age, gender, growth, body composition, genetics, pregnancy, lactation, wound healing and burns, alcohol abuse, infections, and diseases (anemia, coronary artery, Keshan, Kashin-Beck). Additionally, interactions may occur with dietary factors, such as other minerals (iron versus copper), phytates (zinc), oxalates (iron), fiber (manganese), and polyphenolic compounds (molybdenum). On a global basis, requirements can vary according to soil and geographical location, food preparation and processing, food accessibility, cultural practices (geophagia) and pollution. Furthermore, global differences exist in body composition, ethnicity, and age of menarche.

Freeland-Graves, J. H., Sanjeevi, N., and Lee, J. J.,Global perspectives on trace element requirements, J Trace Elem Med Biol, 2015, 31, 135.

 

Molbdate nutritional products

AOAC First Action Method 2011.19: Chromium, Selenium, and Molybdenum in Infant Formula and Adult Nutritional Products, was collaboratively studied. This method employs microwave digestion of samples with nitric acid, hydrogen peroxide, and internal standard followed by simultaneous detection of the elements by an inductively coupled plasma mass spectrometer (ICP-MS) instrument equipped with a collision/reaction cell. During this collaborative study, nine laboratories from four different countries, using seven different models of ICP-MS instruments, analyzed blind duplicates of seven infant, pediatric, and adult nutritional formulas. One laboratory's set of data was rejected in its entirety. The method demonstrated acceptable repeatability and reproducibility and met The Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) standard method performance requirements (SMPR) for almost all of the matrices analyzed. The Cr, Mo, and Se SPIFAN requirement for repeatability was 5% RSD. The SMPR called for a reproducibility of 15% RSD in products for ultratrace element concentrations above the targeted limit of quantitation of 20 mug/kg Cr/Mo and 10 mug/kg Se (as ready-to-feed). During this collaborative study, repeatability relative standard deviation ranged from 1.0%-7.0% and reproducibility relative standard deviation ranged from 2.5-13.4% across all three ultratrace elements.,

Determination of Chromium, Selenium, and Molybdenum in Infant Formula and Adult Nutritional Products - Inductively Coupled Plasma-Mass Spectrometry: Collaborative Study, Final Action 2011.19, J AOAC Int, 2015.

 

Molybdenum intake from diet

The molybdenum intake by German and Mexican adults (21 test populations) aged 20 to 69 years with mixed and ovolactovegetarian diets was determined. Each test group consisted of at least 7 women and 7 men, which collected all consumed foodstuffs and beverages as visually estimated duplicates on 7 successive days.

The balance studies were carried out with 8 test populations (women and men) with mixed and ovolactovegetarian diets.

People with mixed diet in Germany consumed, on average, 89 (women) and 100 μg Mo/day (men), whereas in Mexico they took in 160 (women) and 210 (men) μg Mo/day. German ovolactovegetarians consumed approximately 175 μg Mo/day.

Male adults of Germany consumed 21% more molybdenum than women. This difference is the result of a 24% higher dry matter intake by males.

The residence place, its geological origin and time of examination influenced the molybdenum intake significantly (60-115 μg Mo/day). The normative molybdenum requirement of adults amounts to 25 μg/day, with women needing 20 and men 25 μ g/day.

As a rule approximately only one-third of the absorbed molybdenum is excreted renally, the rest faecally. Breast feeding mothers excreted 11% via milk, 56% faecally and 33% renally.

The apparent absorption rate of molybdenum amounted to 37% in humans with mixed and vegetarian diets, whereas it reached 44% in breast-feeding mothers.

The calculation of molybdenum consumption (basket method) overestimated the molybdenum intake by 50% in comparison to chemical determination by the duplicate portion method

Anke, M., Holzinger, S., Seifert, M., Muller, R., and Schafer, U., The Biological and Toxicological Importance of Molybdenum in the Environment and in the Nutrition of Plants, Animals and Man - Part Iv: the Molybdenum Intake of Adults with Mixed and Vegetarian Diets in Germany and Mexico, Acta Alimentaria, 2010, 39, 1-11.

Molybdate in human serum after exercise

The present study aims to examine how exercise performed until fatigue at night affects element distribution in the serum. The study examined 10 healthy sedentary males who were not actively engaged in any particular sport and whose mean age was 23.00 +/- 0.25 years, mean height 177.79 +/- 2.25 cm, and mean weight 70.70 +/- 1.63 kg. Blood samples were collected from the subjects at midnight twice: during rest before exercise and after exercise. Serum phosphorus, sodium, potassium, sulfur (mmol/L), cobalt, boron, cadmium, chrome, nickel, manganese, molybdenum, copper, iron, zinc and calcium levels (mg/L) were measured using atomic emission spectroscopy (ICP-AES).

Exhaustion exercise performed at night brought about a decrease in copper levels only (p< 0.05), while elevating levels of potassium, sodium, magnesium, calcium, iron, zinc, manganese, nickel, selenium, molybdenum, chrome, cobalt, lead and cadmium (p< 0.05).

The results of the study demonstrate that nighttime exercise until exhaustion significantly alters element metabolism

Patlar, S., Gulnar, U., Baltaci, A. K., and Mogulkoc, R., Effect of Nocturnal Exhaustion Exercise on the Metabolism of Selected Elements, Archives of Biological Sciences, 2014, 66, 1595-1601.

Molybdenum in human blood

Concentrations of molybdenum in whole blood (229 samples from 19 collection sites in the United States) have been determined [Roth, 1968]. The mean concentration ranged from 0.50 to 15.73 microg /100 ml. Similar findings were obtained by Morgan and Holmes in the normal population in England where the whole blood molybdenum concentration range in males was 0.8 ± 0.3 and in females 1.2 ± 0.5 ng/g, and by Nadkarni and Morisson (1976) who found the serum molybdenum concentration to range between 0.012 and 0.034 ng/g of molybdenum [Cilingarajan, 1965].

Roth, M., Arch. Environ. Health, 1968, 16, 340.
Schroeder, H. A., Balassa, J. J.and Tipton,I. H., J. Chronic Diseases, 1970, 23, 481.
Morgan, A.and Holmes, A., Radiochem. Radioanal. Letters, 1972, 9, 329.
Nadkarni, R. A. and Morrison, G. H., Radiochem. Radioanal. Letters, 1976, 24, 103.
Cilingarajan, A. G., Izv. Akad. Nauk Arm. SSR, 1965, 18, 29.

The trace element levels of hospital patients whose bone fractures had received osteosynthetic treatment or had required the use of artificial replacement joints is reported. For molybdenum the immediately preoperative blood plasma level of Mo (0.7 microg/l) was below the normal level (1.20 microg/l) and decreased postoperatively (0.5 microg/l. This marked reduction of the Mo content of the blood plasma is attributed to a shift of Mo into the affected tissue, since the enzymes xanthine oxidase and sulfite oxidase, which require Mo as a cofactor, are essential enzymes of bone and connective tissue metabolism, functioning as part of a detoxification mechanism for accumulated cell debris. The extent of the reduction of the plasma Mo level could be a measure of the wound healing process. A deficiency of Mo due to increased demand from the wound could cause interference in the healing process.

Keller, T, Gehring, L, Grafe, S, Hetzel, G, Loser, T, Electrolyte and trace element status following osteosynthetic Operations, Trace Elements And Electrolytes,1999,16, 4, 183-191.

Most people have whole blood concentrations

Reference ranges of the concentration of trace elements in human serum are established by inductively coupled plasma- mass spectrometry (ICP-MS). The range of Mo concentrations in sera collected from 110 healthy humans was 0.44 +/- 1.62 microg/l.

Forrer, R., Gautschi, K., and Lutz, H., Simultaneous measurement of the trace elements Al, As, B, Be, Cd, Co, Cu, Fe, Li, Mn, Mo, Ni, Rb, Se, Sr, and Zn in human serum and their reference ranges by ICP-MS, Biological Trace Element Research, 2001, 80, 77-93.

Whole blood and serum concentrations of metals in a Swedish population-based sample
Objective.
While the potential toxicity of metals in humans is a well-established field of research, there are few studies that examine circulating concentrations of metals in large population-based samples. The aim of this study was to analyze levels of heavy metals and trace elements in both whole blood and serum in an elderly population, and to examine if gender, kidney function, haemoglobin or serum albumin could impact the distribution of metals between whole blood and serum.

Methods.
Whole blood and serum samples from 1016 70-year-olds living in Uppsala, Sweden, were analyzed for aluminium, cadmium, cobalt, copper, chromium, mercury, manganese, molybdenum, nickel, lead, and zinc using inductively coupled plasma-sector field mass spectrometry (ICP-SFMS).
Distribution between whole blood and serum was evaluated by the ratio between whole blood and serum concentration (B/S-ratio).

Results.
Concentrations differed significantly between whole blood and serum measurements for all 11 metals (p < 0.00001). The highest B/S-ratios were found for lead (27), zinc (9), manganese (6), and nickel (4).
Copper (0.86), cobalt (0.84), and molybdenum (0.86) showed B/S-ratios < 1.
Especially the B/S-ratios for chromium, mercury and nickel correlated with kidney function (GFR) (r = 0.21, - 0.21 and -0.36 respectively, p < 0.0001).

Conclusions.
The distribution between whole blood and serum varied considerably for different metals. This distribution correlated with physiological factors, mainly with kidney function, for several of the metals

Schultze, B., Lind, P. M., Larsson, A., and Lind, L., Whole blood and serum concentrations of metals in a Swedish population-based sample, Scandinavian Journal of Clinical & Laboratory Investigation, 2014, 74, 143-148.

Molybdate levels in humans

Levels of trace elements, aluminium, arsenic, cobalt, copper, iron, lead, manganese, mercury, molybdenum, nickel, selenium and zinc, in whole blood, serum and urine of 61 non-smoking adults living on the west coast of Canada and their association with age, gender, diet, participation in certain hobby and/or occupational activities, and levels of other trace elements are reported..

Trace elements were measured using inductively-coupled plasma mass spectrometry.

Participants estimated their intake of shellfish (oysters, mussels, scallops), organ meats (beef and pork liver, chicken liver, beef kidney), leafy green vegetables (spinach, lettuce, seaweed; cooked and uncooked), potatoes (French fries, chips, boiled, mashed), carrots, and tomatoes (fresh, processed into sauce, ketchup, or juice) in the previous 12 months.

Geometric mean blood molybdenum level was 15.36 nmol l-1 and urine molybdenum was 58.41micromol mol-1 cr-1.

Urine molybdenum levels were generally higher in this study than have previously been measured, possibly due to higher consumption of seafood in this sample.

Molybdenum in urine and blood decreased with increasing with consumption of mashed potatoes and scallops (negative correlation) possibly because potatoes and scallops have less molybdenum than plants growing above the ground, including legumes and leafy vegetables, and so provide less dietary molybdenum. (Barceloux, Barceloux, 1999).

Molybdenum in blood and molybdenum in urine correlated positively
(blood Mo) = 1.2892 + 0.3554 (urine Mo)
—expected as urine is the major excretory path for molybdenum in the body (Turnlund et al.,1995).
There was an inverse correlation of lead in blood with molybdenum in blood and urine. The plot below has been constructed from data in the paper.

Clark, N. A., Teschke, K., Rideout, K., and Copes, R., Trace element levels in adults from the west coast of Canada and associations with age, gender, diet, activities,. and levels of other trace elements, Chemosphere, 2007, 70, 155-164.

Japanese adults with and without liver dysfunction

The serum molybdenum (Mo) concentrations in 70 Japanese adults (35 males and 35 females) not receiving any medical care or treatment were determined by inductively coupled plasma-mass spectrometry.

Serum Mo concentration in the subjects ranged from < 0.1 to 9.11 ng/mL.
More than half (55.7%) of the subjects showed values of less than 1 ng/mL and only 6 (8.6%) subjects showed more than 2 ng/mL.

The mean +/- SD, geometrical mean (GM), range of GM geometrical SD (GSD) and median value were 1.21 +/- 1.34, 0.81, 0.30 to 2.16, and 0.90 ng/mL, respectively. 15 subjects suspected of having liver dysfunction showed significantly higher serum Mo than others.

Reference range of serum Mo in Japanese healthy adults without liver dysfunction: 0.10-4.73 ng/mL, estimated as a range of GM +/- 2GSD.

Yoshida, M., Ota, S., Fukunaga, K., and Nishiyama, T., Serum molybdenum concentration in healthy Japanese adults determined by inductively coupled plasma-mass spectrometry, Journal of Trace Elements in Medicine and Biology, 2006, 20, 19-23.

More than 90% of Mo contained in a routine dietary menu is absorbed, most of Mo absorbed is excreted in urine, and Mo balance is in equilibrium in the general Japanese population. (c) 2006 Elsevier GmbH. All rights reserved

Yoshida, M., Hattori, H., Ota, S., Yoshihara, K., Kodama, N., Yoshitake, Y., and Nishimuta, M., Molybdenum balance in healthy young Japanese women, Journal of Trace Elements in Medicine and Biology, 2006, 20, 245-252.

Molybdenum blood levels in mothers and newborns

The correlation of cord blood levels of molybdenum in newborns with maternal concentrations of molybdenum suggests that molybdenum compounds easily cross the placental barrier [Bougle et al.,1988, 1989].

Bougle, D., Bureau, F., Foucault, P.,. Molybdenum content of term and preterm human milk during the first two months of lactation, Am. J. Clin. Nutr., 1988, 48, 652-654.
Bougle, D., Voirin, J., Bureau, F., Molybdenum normal plasma values at delivery in mothers and newborns, Acta Paediatr. Scand., 1989, 78, 319-320.

Mean plasma level in 33 mothers 1.44 microg Mo/L with a range up to 3 microg Mo/L.
Mean concentration in breast milk in 6 mothers in France 10 microg Mo/L at birth decreasing to 1 microg/L 2 months post-delivery.

Bougle, D., Bureau, F., Foucault, P.,. Molybdenum content of term and preterm human milk during the first two months of lactation, Am. J. Clin. Nutr., 1988, 48, 652-654.
Bougle, D., Voirin, J., Bureau, F., Molybdenum normal plasma values at delivery in mothers and newborns, Acta Paediatr. Scand., 1989, 78, 319-320.

The concentration of molybdenum in the blood of women increased significantly during pregnancy (from 12.95 microg /100 ml after 12-19 weeks' pregnancy to 33.85 microg /100 ml at the time of labour) [Polonskaya, 1966]. The blood of non-pregnant controls contained 16.55 microg Mo/100 ml. For the pregnant women and the control group the daily molybdenum intake was 0.26 mg so the increase in blood molybdenum concentration was probably due to a mobilisation of tissue reserves.

Polonskaya, M. N., Gig. Pitan., 1966, 126.

Plasma studies were conducted in healthy breast-fed infants and in patients with phenylketonuria at the age of 4 weeks, and the plasma investigations were repeated at the ages of 4 and 12 months. Molybdenum concentrations in formulas exceed those in human milk. Molybdenum intake and retention in all infants with phenylketonuria were more than 18 times those of breast-fed infants.The plasma concentrations reflected these differences. A median of 0.04 mu g/l was assessed in breast-fed infants at 4 weeks and less than 0.02 mu g/l at 4 months of age. Comparative results of infants with phenylketonuria were 2.9 mu g/l and 2.5 mu g/l, respectively. There were no significant differences between the groups at 12 months of age. The phenylketonuria diets investigated showed excessive retention and plasma concentrations of the essential trace element molybdenum in early infancy. In view of these findings, the present practice of molybdenum fortification should be revised

Sievers, E., Arpe, T., Schleyerbach, U., and Schaub, J., Molybdenum supplementation in phenylketonuria diets: Adequate in early infancy?, Journal of Paediatric Gastroenterology and Nutrition, 2000, 31, 57-62.

Blood: Human biomonitoring for metals in Italian urban adolescents: Data from Latium Region

As a part of the activities of the first Italian human biomonitoring survey (PROBE - PROgramme for Biomonitoring general population Exposure), a reference population of adolescents, aged 13-15 years, was examined for their exposure to metals. The study included 252 adolescents living in urban areas, representative of Latium Region (Italy) and blood specimens were analyzed for metals (As, Be, Cd, Co, Cr, Hg, It, Mn, Mo, Ni, Pb, Pd, Pt, Rh, Sb, Sn, Tl, U, V and W) by sector field inductively coupled plasma mass spectrometry.

The results obtained will improve the knowledge about the body burden in adolescents and are tentative reference values for Italian young people as a basis for risk evaluation deriving from urban/environmental exposure to metals. (C) 2011 Elsevier GmbH. All rights reserved

Pino, Anna, Amato, Antonio, Alimonti, Alessandro, Mattei, Daniela, and Bocca, Beatrice, Human biomonitoring for metals in Italian urban adolescents: Data from Latium Region, International Journal of Hygiene and Environmental Health, 2012, 215, 185-190.

Blood: Serum metal ion levels after rotating-hinge knee arthroplasty: comparison between a standard device and a megaprosthesis

Purpose The effects of systemic metal ion exposure in patients with implants made of common prosthetic alloys continue to be a matter of concern. The aim of the study was to determine the measurement values of cobalt (Co), chromium (Cr) and molybdenum (Mo) in serum following rotating-hinge knee arthroplasty.

Methods Blood was taken from 25 patients [mean follow-up 35 (range nine to 67) months] treated with megaprostheses (n=17) or standard rotating-hinge devices (n=8) and analysed using electrothermal graphite furnace atomic absorption spectrometry (ET-ASS).

Results Determining the concentrations of metal ions following rotating-hinge knee arthroplasty revealed increments for Co and Cr but not Mo. Metal ion release was significantly higher in patients with megaprostheses compared to a standard rotating-hinge knee device (Co p=0,024; Cr p=0.025).

Conclusion The authors believe there might be an additional metal ion release from the surface of the prosthesis and not only from the articulating surfaces because, in cases of rotating-hinge knee prosthesis, there is a metal-on-polyethylene articulation and not a direct metal-on-metal junction. Nevertheless, long-term studies are required to determine adverse effects of Co, Cr and Mo following total hip replacement and total knee arthroplasty

Friesenbichler, Joerg, Maurer-Ertl, Werner, Sadoghi, Patrick, Lovse, Thomas, Windhager, Reinhard, and Leithner, Andreas, Serum metal ion levels after rotating-hinge knee arthroplasty: comparison between a standard device and a megaprosthesis, International Orthopaedics, 2012, 36, 539-544.

Simultaneous Determination of 10 Ultratrace Elements in Infant Formula, Adult Nutritionals, and Milk Products by ICP/MS After Pressure Digestion: Single-Laboratory Validation

A single-laboratory validation (SLV) is presented for the simultaneous determination of 10 ultratrace elements (UTEs) including aluminum (Al), arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), mercury (Hg), molybdenum (Mo), lead (Pb), selenium (Se), and tin (Sn) in infant formulas, adult nutritionals, and milk based products by inductively coupled plasma (ICP)/MS after acidic pressure digestion. This robust and routine multielemental method is based on several official methods with modifications of sample preparation using either microwave digestion or high pressure ashing and of analytical conditions using ICP/MS with collision cell technology. This SLV fulfills AOAC method performance criteria in terms of linearity, specificity, sensitivity, precision, and accuracy and fully answers most international regulation limits for trace contaminants and/or recommended nutrient levels established for 10 UTEs in targeted matrixes.

Dubascoux, S., Nicolas, M., Rime, C. F., Payot, J. R., and Poitevin, E.,Simultaneous Determination of 10 Ultratrace Elements in Infant Formula, Adult Nutritionals, and Milk Products by ICP/MS After Pressure Digestion: Single-Laboratory Validation, Journal of Aoac International, 2015, 98, 953-961.

Molybdenum in human milk

Molybdenum microg/l in term and preterm milk during 21 days of lactation

Molybdenum in human milk
 2-6 d12-16 d21 d
term milk 6.82.5 5.72.3 3.61.4
preterm milk 3.91.4 2.41.1 1.90.9
 
Blood content 1 d 21  
term newborns 4.70.3 4.20.3  
preterm newborns 1.80.5 1.50.3  

Aquilio, E., Spagnoli, R., Seri, S. Bottone, G., Spennati, G., Trace-Element Content In Human-Milk During Lactation Of Preterm Newborns, Biological Trace Element Research, 1996, 51, 63-70.

Molybdenum in human milk from lactating mothers of premature and full-term living in Newfoundland, Canada, showed a definite decrease with time, suggesting that the Mo content in milk is homeostatically regulated. [Friel et al., 1999.]

Friel, J.K., Andrews, W.L., Jackson, S.E., Longerich, H.P., Mercer, C., McDonald, A., Dawson, B., Sutradhar, B., Elemental composition of human milk from mothers of premature and full-term infants during the first 3 months of lactation, Biological Trace Element Research, 1999, 67, 225-247.

19 mothers were assessed daily over 2 to 8 weeks.

Transfer factor: the element concentration in food (g/kg) divided by the element concentration in milk (g/l)

Elements in food and milk
LaCeTiNbThCrMoURuCoAgGaSb
13.8 16.1 5.6 20.7 20.2 6.9 77.4 21.3 4.1 8.4 5.1 19.1 13.2


Factors differed across individuals, the result of individual differences in milk production and factors other than the amount of any particular element absorbed by the body.

Wappelhorst, O., Kuhn, I., Heidenreich, H., and Markert, B., Transfer of selected elements from food into human milk, Nutrition, 2002, 18, 316-322.

The molybdenum concentration in human mature milk from 241 subjects who resided in cities in state, former Uttar Pradesh, India. The overall mean value for the molybdenum content of mature human milk was 0.018 ppm Mo. Most of the individual values for molybdenum in human milk fell within the narrow range of 0.007 to 0.033 ppm Mo. A geographical variation was attributed to differences in the molybdenum content of food items consumed by the residents of different communities.

Pandey, R., Singh, U., and Singh, S. P., Geographical distribution of molybdenum in human milk, Journal of Advanced Zoology, 2003, 24, 8-10.

Molybdenum in the breast milk and plasma of lactating women

The trace element content of breast milk and plasma in 209 lactating women in the UAE was determined using ICP-MS. The concentrations of trace elements in blood and breast milk were little different between women from the UAE and those from elsewhere. Molybenum (and chromium and arsenic) increased with increasing age of the infant, while manganese, copper and zinc decreased. with increasing age of the infant. The trace element concentrations of breast milk and maternal blood were comparable to published values. Normal values for plasma and breast milk trace metal concentrations have been obtained for UAE women.

Molybdenum concentrations/microg L−1 were:
In plasma: range 0.001―2.05, mean 0.281, median 0.270;
In breast milk: range 0.001―1.9, mean 0.348, median 0.061

Abdulrazzaq, Y. M., Osman, N., Nagelkerke, N., Kosanovic, M., and Adem, A., Trace element composition of plasma and breast milk of well-nourished women, Journal of Environmental Science and Health Part A-Toxic/Hazardous Substances & Environmental Engineering, 2008, 43, 329-334.

Molybdate in breast milk from Japanese women

Molybdenum and chromium in 79 Japanese breast milk samples were measured by inductively coupled plasma-mass spectrometry. The molybdenum concentration in 51 samples (64.6%) was less than 5 nag/ml and in only 12 samples (15.2%) was more than 10ng/ml. The range was <0.1 to 25.91 and the median was 3.18 ng/ml.

Data on the secretion of trace elements in human milk is needed to estimate intake by breast-fed infants and to establish the recommended intake for infants. For some trace elements adequate intake (AI) levels for infants are in “Dietary Reference Intakes for Japanese, 2005” (DRI-J 2005) but not for molybdenum (or chromium) because of the lack of information of their concentrations in breast milk. The aim of the investigation was to obtain and estimate of AI levels of Mo and Cr in Japanese infants. The derived AI for Japanese infants (0 to 5 months) was 2.5 microg Mo/day. A detailed account of the statistical treatment of the measurements and the calculation of the AI is given in the paper.

Yoshida, M., Takada, A., Hirose, J., Endo, M., Fukuwatari, T., and Shibata, K., Molybdenum and chromium concentrations in breast milk from Japanese women, Bioscience Biotechnology and Biochemistry, 2008, 72, 2247-2250.

Human tissues and organs

In healthy individuals, the average molybdenum content in the liver and kidneys determined spectrographically was 1.0 and 0.3 mg/kg respectively [Tipton and Cook, 1963]. The molybdenum content in the cortex of suprarenals of males 51-62 years old was 0.20 microg/kg, in the liver 0.88 microg/kg and in the myocardium 0.022 microg/g [Plantin, 1972]. In a report from the former U.S.S.R., the molybdenum concentration in the liver of normal individuals 17-77 years old was found to range between 0.54 and 0.64 microg/g of which 0.22 and 0.24 microg/g was found in the kidneys [Pribluda, 1964]. It has been reported that the molybdenum content in the human embryonic membranes specifically the amnion contains on average 3.50 ± 0.27 microg/g and the chorion 0.60 ± 0.02 microg/g molybdenum in ash.

Tipton, I. H. and Cook, M. J., Health Phys., 1963, 9, 103.
Plantin, L. O., WHO/IAEA Progress Report, Stockholm ,1972.
Pribluda, L. A., Vest. Akad. Nauk BSSR, Serie, 1964, 4, 133.
Sievers, E., Arpe, T., Schleyerbach, U., and Schaub, J., Molybdenum supplementation in phenylketonuria diets: Adequate in early infancy?, Journal of Paediatric Gastroenterology and Nutrition, 2000, 31, 57-62. Molybdenum in human milk

Molybdenum Concentrations in Adult Human Organs

Molybdenum Concentrations in Adult Human Organs
 BrainKidneyLiverLungMuscleSpleen
Adult human 0.14 1.6 3.2 0.15 0.14 0.20

Concentrations in ppm Mo on dry weight basis.

Tipton, I. H. and Cook, M. J., Trace Elements in Human Tissue. Part II Adult Subjects from U.S., Health Phys.,1963, 9,103.
Underwood, E. J., Trace Elements in Human and Animal Nutrition, 2nd Ed. 1962, 100. Academic Press, London.
Kolomiitseva, M. G., Polonskaya, M. N. and Osipov, G. K.,Mikroelem. Sel. Khoz. Med., 1968, 4, 183; Tipton, I. J., J. Chronic Dis., 1970, 23, 481.

Molybdenum Concentrations in Human Tissues

Molybdenum Concentrations in Human Tissues
 Concentration/microg (g ash)-1
TissueFraction ObservedMedian Concentration
Adrenal 10/13 15
Lung 5/141 <4
Lung, S.F. 23/27 2
Larynx 1/50 <4
Trachea 1/60 <4
Skin 2/22 <4
Esophagus 1/66 <4
Stomach 11/130 <4
Duodenum 6/67 <4
Jejunum 7/102 <4
Ileum 18/83 <4
Cecum 6/31 <4
Sigmoid Colon 4/108 <4
Rectum 2/42 <4
Omentum 12/75 <4
Bladder 6/110 <4
Kidney 140/144 31
Liver 147/147 75
Pancreas 12/139 <4
Spleen 4/143 <4
Muscle 2/136 <4
Diaphragm 3/91 <4
Heart 8/140 <4
Aorta 3/104 <4
Uterus 1/32 <4
Ovary 0/16 -
Postrate 2/50 <4
Testis 2/72 <4
Thyroid 1/21 <4
Brain 3/129 <4
Fat 27/27 5
Bone 1/91 <4

Tipton, I. H. and Cook, M. J., Trace Elements in Human Tissue. Part II Adult Subjects from U.S., Health Phys.,1963, 9,103.
Yoo, Y.C., Lee, S. K., Yang, J. Y., In, S. W., Kima, K. W., Chung, K. H., Chung, M. G., and Choung, S. Y., Organ distribution of heavy metals in autopsy material from normal Korean, Journal of Health Science, 2002, 48, 186-194.

Molybdenum in human cadavers

The concentrations of aluminum, arsenic, cadmium, chromium, copper, iron, lead, manganese, mercury, molybdenum, nickel, selenium, silicon, tin, vanadium and zinc were determined in 89 male and 61 female Korean cadavers of ages from 12 to 87 years. Mean Mo concentrations were:

Molybdenum in human cadavers
TissueMean/microg Mo
(g wet weight)-1
Standard Deviation
Liver 0.73 0.37
Kidney 0.27 0.14
Heart 0.09 0.10
Lung 0.10 0.11
Spleen 0.08 0.10
0.06 0.09 0.10
Cerebmm 0.05 0.07
Bone 0.09 0.14
Hair 0.25 0.28
Nail 1.9 2.5

Prenatal molybdenum exposure and infant neurodevelopment in Mexican children

Objective:
To evaluate the association between prenatal exposure to molybdenum (Mo) and infant neurodevelopment during the first 30 months of life. Methods:

We selected a random sample of 147 children who participated in a prospective cohort study in four municipalities in the State of Morelos, Mexico. The children were the products of uncomplicated pregnancies with no perinatal asphyxia, with a weight of >= 2 kg at birth, and whose mothers had no history of chronic illnesses. These women were monitored before, during, and after the pregnancy.

For each of these children a maternal urine sample was available for at least one trimester of pregnancy, and urine Mo levels were determined by electrothermal atomic absorption spectrometry.

Neurodevelopment was evaluated using the psychomotor (PDI) and mental development indices (MDI) of the Bayley scale.

Association between prenatal exposure to Mo and infant neurodevelopment was estimated using generalized mixed effect models.

Results:
The average urinary concentrations of Mo adjusted for creatinine varied between 45.6 and 54.0 mu g/g of creatinine at first and third trimester, respectively. For each doubling increase of Mo (mu g/g creatinine) during the third trimester of pregnancy, we observed a significant reduction on PDI (beta = -0.57 points; P = 0.03), and no effect on MDI (beta = 0.07 points; P = 0.66).

Discussion:
As this is the first study that suggests a potential negative association between prenatal Mo exposure and infant neurodevelopment, these results require further confirmation

Vazquez-Salas, R. A., Lopez-Carrillo, L., Menezes, J. A., Rothenberg, S. J., Cebrian, M. E., Schnaas, L., Viana, G. F. D., and Torres-Sanchez, L., Prenatal molybdenum exposure and infant neurodevelopment in Mexican children, Nutritional Neuroscience, 2014, 17, 72-80.

Industrial and Environmental Exposure of Humans

Humans are exposed to molybdenum compounds in industrial operations and in the environment. As with other elements maximum exposure limits for molybdenum are laid down in government legislation and regulatory controls. The limits may vary from country to country and are not always consistent. The basis for the limits is not always clear. Here we list the regulatory limits, the natural levels of molybdenum and the levels derived from industrial activity including mining.

Mo uptake from industrial sources

Average daily intakes of Mo 0.1 – 0.5 mg Mo increasing to 1 mg if contamination from industrial sources

Friberg, L., Lener, J., Molybdenum, in Handbook on the Toxicology of Metals Vol II, Friberg, L., Nordberg, G.F., and Vouk, V.B., eds., Elsevier, 1986, 446 – 461.

56 adults in Germany 47 – 89 microg

Anke, M., Groppel, B., Krause, U., Arnhold, W., Langer, M., Trace element intake of humans , J. Trace Elemen. Electrolytes Health Dis., 1991, 5, 69 – 74.

Adults in Denver 120 – 240 microg Mo/d av 180

Tsongas, T.A., Meglen, R.R., Walravens, P.A., Chappell W.R., Molybdenum in the diet, Am. J. Clin. Nutr., 1980, 33, 1103 –1107.

NE US 74 – 126 microg Mo/d

Pennington, J.A.T., Young, B.E., Wilson, D., Nutritional elements in US diets, J. Am. Diet. Assoc., 1989, 89, 659 – 664.

For guinea pigs exposed to the dust or fumes of molybdenum trioxide (150-300 mg/m3) for 1 h per day, 5 times per week, for 5 weeks [Fairhall et al., 1945]. Low concentrations of molybdenum (20-270 microg/10g fresh tissue) were found in the lungs, liver, kidneys, spleen and bone. The molybdenum concentrations in these tissues decreased after exposure was stopped to 20% of the original level after 2 weeks. After an oral gavage dose of 50 mg molybdenum trioxide was administered to guinea pigs, molybdenum was distributed to the kidneys, spleen, blood, bile, liver, and lungs within 4 h. The concentrations of molybdenum in the organs decreased, whereas in the blood and bile molybdenum titres were higher at 48 h. Bone retained molybdenum longer than any other tissues [Fairhall et al., 1945]. Based on the amount recovered in faeces for up to 48 h, Fairhall et al. (1945) calculated that 85 % of the oral dose was absorbed. Excess hexavalent forms of molybdenum are excreted rapidly through the kidneys and the bile. Twice as much molybdenum is eliminated in urine as in the faeces. The urinary and faecal concentrations of molybdenum returned to normal after an oral dose of molybdenum trioxide was administered to guinea pigs [Fairhall et al., 1945]. The predominant urinary metabolite of molybdenum was in the form of molybdate complexes [Venugopal and Luckey, 1978].

Fairhall, L. T., Dunn, R. C., Sharpless, N. E. and Pritchard, E. A., U. S. Public Health Bull., 1945, 293, 1.
Venugopal, B. and Luckey, T. D., Metal Toxicity in Mammals, 1978, Vol. 2, Chemical Toxicity of Metals and Metalloids, Plenum Press, New York.

Regulatory controls and legislation

Threshold Limit Values of Some Common Metals
 TLV/mg Mo/m3
Metalsolubleinsoluble
molybdenum 5 10
tungsten 1 5
iron oxide   5
tantalum   5
nickel 0.1 1
copper dust 1 1
copper fume   0.2
chromium   0.5
lead 0.15 0.15
cobalt 0.02 0.02
chromium(VI) 0.05 0.01
cadmium 0.01 0.01
arsenic 0.01 0.01

TLV, threshold limit value
International Molybdenum Association (IMOA), Report 1995, p. 5

Molybdenum Regulatory Limits
Process or materialLimitUnitsAveraging periodSource of limit
Air emission
Dust collectors 15 mg Mo dust/m3   Holland-permit
Calciner dust collector 0.126 kg Mo oxide/h   Holland-permit
Dryer dust collector 0.024 kg ADM/h   Holland-permit
As dust 10 mg/m3   NER (Dutch emission guidelines)
Soluble compounds 5 mg Mo/m3   UK Health and Safety Executive
Insoluble compounds 10 mg Mo/m3   UK Health and Safety Executive
Exhaust air from production plants 5 mg Mo/m3 0.5 - 3 h total Austria
For non-ferrous metals after filter stations 0.2 mg Mo/m3 0.5 - 3 h Austria-regional authority
Soluble Mo TLV 5 mg Mo/m3 0.5 - 3 h Austria
Insoluble Mo TLV 15 mg Mo/m3 0.5 - 3 h Austria
Water quality
Drinking 0.07 mg/l   Austria-WHO guideline
  0.01 mg/l   Chile-N Ch 1333 - 1978
Industrial 1 - 2 kg/day   Holland-permit
  5 mg/l   Austria-country
  5 mg/l 2 h average Germany-municipal authorities
Ground 300 mg/l   Holland-intervention values
  5 ppm   Holland-authorisation
  none     Belgium-80/68/EEC
  0.1 mg/l   US EPA
  0.07 mg/l   Japan
target limit 5 mg/l   Belgium-MILBOWA (DBO 07494013)
intervention limit 300 mg/l   Belgium-MILBOWA (DBO 07494013)
Soil
soil sanitation 200 mg/kg   Holland-intervention values
arableland pastures 10 mg/kg dry   Austria-TLV
  30 kg/ha   Austria-TLV
  3 g/m2   Austria-TLV
target limit 10 mg/kg dry   Belgium-MILBOWA (DBO 0749013)
intervention limit 200 mg/kg dry   Belgium-MILBOWA (DBO 0749013)
emission limit 150 mg/kg dry   Belgium-MILBOWA (DBO 0749013)
Solid waste
waste 5000 mg/kg   Holland-(BAGA)
to landfill 50 mg/l   Germany-approval DIN 38414
landfill leachate limit 125 mg/kg dry   OVAM proposals to Belgium Government
leachate limit 35 mg/m2   OVAM proposals to Belgium Government
  150 mg/m3/100y   Belgium-NEM 7340 Decision 23/11/95
sludge from dredging 10 mg/kg dry   Belgium-Decision 25/11/93
fly ash leachate limit 3 mg/kg   Belgium- NEM 7343 Decision 20/1/93
Sewage sludge
agricultural disposal 20 mg/kg dry   Austria
  0.5 mg/l   Chile
land application ceiling concentration 75 mg/kg   US EPA
Milk
  0.2 mg/kg   Austria

Data assembled by IMOA Health and Safety Committee, 1999.

MAC Limits for Insoluble and Soluble Molybdenum Compounds
CountryMAC Limit (mg/m3) 
Insoluble molybdenum compounds
Holland 10 (mean)  
Romania 5 (mean)  
Germany 15 (mean)  
Russia (USSR), Hungary, Bulgaria 6 (peak)  
USA 20 (peak) 10 as TWA
Soluble molybdenum compounds
Holland 5 (mean)  
Romania 2 (mean)  
Germany, USA, Austria, Belgium, Italy 5 (mean)  
Russia (USSR), Bulgaria, Poland 4 (peak)  
Romania, USA 10 (peak) 5 as TWA

ILO, Occupational Exposure Limits, 2nd (revised) Ed., Occupational Safety and Health Series, 1980, 37, ILO Geneva.

Workplace Exposure TLV USA
MaterialTLV-TWA /mg m-3
Soluble Mo
respirable particulate

0.5
Insoluble Mo
inhalable particulate
respirable particulate

10
3

Threshold Limit Values and Biological Exposure Indices for 2001: American Conference of Governmental Industrial Hygienists (ACGIH), Cincinatti, Ohio, 2001.

Notes

The number of workers in the United States potentially exposed to molybdenum trioxide during the years 1981 to 1983 was approximately 17,072

National Occupational Exposure Survey (NOES): National Institute for Occupational Safety and Health (NIOSH), 1995.

Occupational standards of exposure established by the Occupational Safety and Health Administration (OSHA) are 5 mg/m3 for soluble molybdenum compounds and 15 mg/m3 for insoluble molybdenum compounds

Hammond, P.B. and Beliles, R.P. Metals. In Casarett and Doull's Toxicology:The Basic Science of Poisons ,ed. Doull, J., Klaasen C. D. and Amdur, M. O., Macmillan, New York, 2nd Ed. 1980, 409.

The American Conference of Governmental Industrial Hygienists [ACGIH, 1995, 2001] recommends a threshold limit value-time-weighted average of 5 mg/m3 for soluble molybdenum compounds and 10 mg/m3 for insoluble molybdenum.

Toxicity of Molybdenum towards Humans

Data on the occurrence and toxicity of molybdenum 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.

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.

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.

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.

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.

Results:

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

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.

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.

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 1.1.1.204) 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.

Polyoxomolybdate

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.

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.