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Abstract for I03038

Range-Finding Report on Immunotoxicity of Sodium Tungstate Dihydrate in Female B6C3F1/N Mice

CASRN: 10213-10-2
Chemical Formula: O4W.2Na.2H2O
Molecular Weight: 329.846
Report Date: October 2012

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.

Tungsten is a high production volume metal that is used in a variety of commercial applications. In addition, tungsten has military applications as a replacement for lead in small caliber ammunition and as a substitute for depleted uranium in armor penetrators. Tungsten is also found in dietary supplements and has potential clinical use as an anti-diabetic therapy. The naturally occurring form of tungsten is sodium tungstate dihydrate, which is water-soluble. As such, this form of tungsten is most frequently encountered in ecological and biological systems and may be present in many food products including wine, mineral water, beer, tea, and coffee (Minoia et al., 1994). Tungsten was nominated to the National Toxicology Program in 2002 by the Centers for Disease Control and Prevention for toxicity and carcinogenicity evaluation.

A case of acute tungsten poisoning has been reported in which an individual consumed alcohol that had been rinsed through a hot gun barrel (Marquet et al., 1997). The individual subsequently experienced nausea, seizures, encephalopathy, and renal failure. Overall, there is inadequate data to assess the potential adverse human health effects of tungsten exposure. Furthermore, the effects of STD on the immune system are also largely unknown. In vitro studies have demonstrated an increase in the apoptosis of peripheral blood lymphocytes following exposure to STD (Osterburg et al., 2010). In 2001-2002, the National Center for Environmental Health (NCEH) conducted a study in Churchill County, Nevada, due to a cluster of cases of acute lymphoblastic leukemia and found elevated concentrations of tungsten in the drinking water and in the urine of study participants (Walker et al., 2012). However, elevated urinary tungsten levels did not differ between case and comparison children and families. A recent study in C57BL/6 mice has suggested that exposure to STD and respiratory syncytial virus may produce leukemia (Fastje et al., 2012). Furthermore, these authors reported neutrophilia to occur following exposure to STD alone. Another study in C57BL/6 mice has indicated that, following 28 days of exposure to STD, tungsten levels were elevated in the bones of exposed mice (Guandalini et al., 2011), suggesting the possibility for effects on the bone marrow.

NTP requested that a dose range-finding study be performed to establish the potential effects of STD on the immune system. These studies were conducted in female B6C3F1/N mice. Five STD concentrations (125, 250, 500, 1000 and 2000 mg/L) were utilized and administered for 28 days via the drinking water. STD solutions in tap water were freshly prepared every two weeks, and stock solutions were stored refrigerated.

Female B6C3F1/N mice exposed to STD in the drinking water demonstrated no effects on body weight, body weight gain or the weights of major organs of the immune system, the thymus and the spleen, over the 28-day exposure period. Total splenocyte number and both absolute values and percent values of spleen cell phenotypes were unaffected by STD exposure. No effects were observed on T-dependent antibody responses, as evaluated using the antibody-forming cell response, the sheep red blood cell enzyme-linked immunosorbent assay, and the keyhole limpet hemocyanin ELISA, suggesting that STD exposure does not adversely affect humoral immunity. Although some significant differences were observed in two ex vivo cell-mediated assays (i.e. the mixed leukocyte response and the cytotoxic T-lymphocyte response), these differences were not dose-responsive. Furthermore, no effects were observed on the in vivo delayed-type hypersensitivity response to C. albicans or in the anti-CD3 mediated proliferation assay, which are two additional assays used to evaluate cell-mediated immunity, suggesting overall that drinking water exposure to STD does not affect cell-mediated immunity. Finally, innate immunity was not affected by STD exposure, as indicated by a lack of effect on both natural killer cell activity and the functional activity of the mononuclear phagocytic system. Bone marrow cell numbers were increased at the 2000 mg/L dose in one study but were unaffected in a second study. Absolute bone marrow cell differentials were increased at the 2000 mg/L dose for all markers evaluated, except for the CD3+ population, which was unaffected. When evaluated as percent values, bone marrow cell differentials were unaffected overall, with the exception of an increase in TER-119+ cells (i.e., erythroid lineage cells) at the 2000 mg/L STD exposure level. In summary, with the exception of effects on bone marrow differentials at the 2000 mg/L dose level, STD did not adversely affect, innate immunity, humoral immunity or cell-mediated immunity in female B6C3F1/N mice exposed via the drinking water.

References

Minoia C., Sabbioni E., Ronchi A., Gatti A., Pietra R., Nicolotti A., Fortaner S., Balducci C., Fonte A., & Roggi C. (1994). Trace element reference values in tissues from inhabitants of the European Community. IV. Influence of dietary factors. Sci Total Environ, 141: 181-95.

Marquet P., François B., Lotfi H., Turcant A., Debord J., Nedlec G., & Lachâtre G. (1997). Tungsten determination in biological fluids, hair and nails by plasma emission spectrometry in a case of severe acute intoxication in man. J Forensic Sci, 42(3):527-30.

Osterburg A.R., Robinson C.T., Schwemberger S., Mokashi V., Stockelman M., & Babcock G.F. (2010). Sodium tungstate (Na2WO4) exposure increases apoptosis in human peripheral blood lymphocytes. J Immunotoxicol, 7(3):174-82.

Walker M., Pritsos C., and Seiler R. (2012). Review of the Churchill County, NV ALL cluster, 1997-2004. Chem Biol Interacti, 196(3):52-8.

Fastje C.D., Harper K., Terry C., Sheppard P.R., and Witten M.L. (2012). Exposure to sodium tungstate and respiratory syncytial virus results in hematological/immunological disease in C57Bl/6J mice. Chem Biol Interact; 196(3):89-95

Guandalini G.S., Zhang L., Fornero E., Centeno J.A., Mokashi V.P., Ortiz P.A., Stockelman M.D., Osterburg A.R., and Chapman G.G. (2011). Tissue distribution of tungsten in mice following oral exposure to sodium tungstate. Chem Res Toxicol, 24:488-493.