Experimental Studies of Molybdenum Physiology and Toxicity
Molybdenum and cancer
Molybdenum trioxide has been reported to be weakly carcinogenic in mice in a short-term (30 week) lung adenoma assay at high doses (4 750 mg/kg total) but not at lower doses [Stoner et al., 1976]. The reported carcinogenicity of molybdenum orange pigment (a mixture of lead chromate and lead molybdate) injected subcutaneously injection to rats is likely due to the lead and chromium rather than the molybdenum since lead chromate is a carcinogen [Maltoni (a), 1976; Maltoni (b), 1976].
Stoner, G. D., Shimkin, M. B., Troxell, M. C., Thompson, T. L. and Terry, L. S., Cancer Res., 1976, 36, 1744.
Maltoni, C., Ann. N.Y. Acad. Sci., 1976, 271, 431.
Maltoni, C., Ann. N.Y. Acad. Sci., 1976, 271, 444.
In the rat azoxymethane induced aberrant crypt foci have been suggested to be biological precursors to colon cancers. The effects of 41 potential chemopreventive agents in the F344 rat using the inhibition of carcinogen-induced aberrant crypt foci in the colon as the measure of efficacy were assessed [Wargovich et al., 1996]. Aberrant crypt foci were induced by the carcinogen azoxymethane. Twenty-three agents did not inhibit aberrant crypt foci; among these were several agents, including sodium molybdate, that promoted the development of aberrant crypt foci at one or both doses tested. The average yield of aberrant crypts for the azoxymethane-only group was 88 8 aberrant crypt foci/colon. When the diet included sodium molybdate (0.05 g/kg diet) the yield of aberrant crypts was 103 8 significantly greater than control group.
Wargovich, M.J., Chen, C.D., Jimenez, A., Steele, V.E., Velasco, M., Stephens, L.C., Price, R., Gray, K., Kelloff, G.J., Aberrant Crypts As A Biomarker For Colon-Cancer - Evaluation Of Potential Chemopreventive Agents In The Rat, Cancer Epidemiology Biomarkers & Prevention, 1996, 5, 355-360.
The potential toxicities of organic and some inorganic compounds have been predicted by a computer program which correlates toxicity with molecular properties [Lewis et al.,1996]. The program is called COMPACT (Computer Optimised Molecular Parametric Analysis for Chemical Toxicity: CYP1A and CYP2E1). Evaluations were also made by Hazard expert, and for metal ion redox potentials; and these, together with COMPACT, were compared with results from the Ames test for mutagenicity in Salmonella, the micronucleus test and 90-day subchronic rodent pathology. According to the abstract, molybdenum trioxide is a metal compound with a redox potential of the metal/metal ion indicative of possible carcinogenicity and the prediction for carcinogenicity was positive for molybdenum trioxide. However, it is clear from the body of the paper that this statement is most misleading. The programs gave no prediction for molybdenum trioxide. The reference to the redox potential is to the Mo(III)/Mo(IV) couple allegedly 0.32 V oxidising and so having carcinogenic potential. This potential is hardly relevant since MoO3 is Mo(VI) and the relevant potential is Mo(VI)/Mo(V), 0.4 V.
Lewis, D.F.V., Ioannides, C., Parke, D.V., Compact And Molecular-Structure In Toxicity Assessment - A Prospective Evaluation Of 30 Chemicals Currently Being Tested For Rodent Carcinogenicity, Environmental Health Perspectives, 1996, 104, 1011-1016.
Cobalt sulfate hydrate, gallium arsenide, molybdenum trioxide, vanadium pentoxide, and nickel sulfate heptahydrate were tested in the Syrian hamster embryo (SHE) assay in order to increase the SHE assay database for heavy metals [Kerckaert et al., 1996]. All five compounds produced significant morphological transformation {MT) at one or more doses in a dose-responsive manner. Cobalt sulfate hydrate, gallium arsenide, molybdenum trioxide, and nickel (II) sulfate heptahydrate were all positive with a 24-h exposure, suggesting direct DNA perturbation. Vanadium pentoxide was negative with a 24-h exposure, but positive with a 7-day exposure. This pattern of response (24-h SHE negative/7-day SHE positive) has been seen with other chemicals which have tumour promotion-like characteristics. MoO3 in a 24 h exposure to SHE cells with culture medium as the solvent gave a significant increase in SHE cell MT in four doses =/> 75 microg/ml and 67% cytotoxicity at the top dose of 200 microg/ml. The Mo value compares with Ni 5 microg/ml and Co 1 microg/l.
Kerckaert, G.A., Leboeuf, R.A., Isfort, R.J., Use Of The Syrian-Hamster Embryo Cell-Transformation Assay For Determining The Carcinogenic Potential Of Heavy-Metal Compounds, Fundamental And Applied Toxicology, 1996, 34, 67-72.
Chronic exposure of animals to molybdenum oxide fumes (53 mg/m3 for 1 h daily) produced pulmonary irritation and fatty changes in the liver and the kidney, but no deaths occurred [Smyth, 1956.]
Smyth, H.E., Hygienic standard for daily inhalation. Ind Hyg Q, 1956,17,129-185.
The results of a study of the respiratory effects of inhalation of air-borne MoO3 dust during two years are summarised in Table 7.2 [Chan et al., 1998]. Although the blood concentration of Mo increased as a consequence of the Mo exposure toxic symptoms were not observed. Prolonged inhalation of MoO3 dusts was harmful to the respiratory system of the mice and rats. The effect of MoO3 is similar to that of talc, nickel oxide and nickel subsulfide and irritants generally in inhalation studies. There is, however, a species dependence and some of the effects are marginal. Whether inhalation of MoO3 induces carcinomas is of particular interest. The number of animals experiencing adenoma or carcinoma at the highest MoO3 exposures were: male mice 9/50 and 10/50, female mice 9/49 and 6/49; male rats 3/50 and 1/50, female rats 2/50 and 0/50. The exposure (100 mg m-3) is ten times the US workplace threshold limit value. The authors comment that MoO3 is not mutagenic.
Chan, P.C., Herbert, R.A., Roycroft, J.H., Haseman, J.K., Grumbein, S.L.,Miller, R.A., Chou, B.J., Lung tumor induction by inhalation exposure to molybdenum trioxide in rats and mice, Toxicological Sciences, 1998, 45, 58-65.
Anti-cancer properties of molybdenum
Sodium molybdate administered in drinking water has a protective action against the induction of cancer in rats by organic N-nitroso compounds [Luo , X.-M.et al.,1983]. Inhibitory effects of molybdenum on oesophageal and forestomach carcinogenesis in rats have been reported [Komada, H. et al., 1990] and the effect of dietary molybdenum on oesophageal carcinogenesis in rats induced by N-methyl-N-benzylnitrosamine [Wei, H.-J et al., 1985]. Effects of molybdenum and tungsten on mammary carcinogenesis are found in SD rats.[ Seaborn and Yang, 1993]. Molybdenum supplementation affects N-nitroso- N-methylurea-induced mammary carcinogenesis and molybdenum excretion in rats [Kopf-Meyer, 1979].
Luo, X. M., Wei, H. J. and Yang, S. P., J.Nat.Cancer Inst.,1983, 71, 75.
Komada, H., Nakagawa, M., Yamamura, M., Hioki, K. and Yamamoto, Cancer Res., 1990, 50, 2418.
Wei, H. J., Luo, X. M. and Yang, S. P., J.Nat.Cancer Inst., 1985, 74, 469.
Seaborn, C. D. and Yang, S. P., Biol. Trace Elem. Res., 1993, 39, 245.
Kopf-Meyer, P., Naturforsch., 1979, 34, 1174.
Molybdenum dichloride has anti-tumour agent properties [Koizumi et al., 1995]. Suppressive effects of molybdenum on hepatotoxicity of N-nitrosodiethylamine in rats have been reported.
Koizumi, T., Tajima, K., Emi, N., Hara, A., Suzuki, K.T., Suppressive Effect Of Molybdenum On Hepatotoxicity Of N-Nitrosodimethylamine In Rats, Biological & Pharmaceutical Bulletin, 1995, 18, 460-462.
The beneficial effect of the molybdenum is due to the denitrosation of the nitroso compound. Molybdenum is also a biological antagonist of cancer-producing copper [Nederbragt, 1982].
Nederbragt, H., Br. J. Nutr., 1982, 48, 353.
Molybdenum prevents the carcinogenesis of N-nitroso compounds [Koizumi et al., 1995]. Male Wistar rats weighing 170-190 g were pretreated with sodium molybdate, Na2MoO4 (1.24 mmol/kg body weight, i.p., once a day) for 3 d and on day 4, they were exposed to N-nitrosodimethylamine (50 mg/kg body weight, once, i.p.). Na2MoO4-pretreatment prevented both nitrosodimethylamine-induced DNA damage and disruption of the metabolism of K and Ca but rather enhanced lipid peroxidation.Mo prevented N nitrosodimethylamine-induced DNA damage by preventing disruption of intracellular Ca metabolism while stimulating the metabolism of the nitroso compound via a nontoxic pathway.