12-wolframosilicic acid

Endpoint summary

Description of key information

Toxicokinetics

There is no data on tungstosilicic acid. The tungsten component is likely to be the main determinant of toxicity and therefore data available for soluble tungstate compounds is used as an indicator of possible toxicity. The information below is from a review prepared by Karen Haneke (Integrated Laboratory Systems Inc) for NIEHS in 2003 which in turn used HSDB and reviews byLangård (2001) and Lagarde and Leroy (2002) plus the ATSDR 2005 review. This is supplemented by a recently published review that was designed to fill in the knowledge gaps since the NIEHS 2003 review (Lemus, 2015).

Adsorption

When rats were orally administered diets containing tungsten as finely ground metal, sodium tungstate, tungsten trioxide, or ammonium paratungstate (doses not provided) for 100 days, tungsten mainly accumulated in bone and in spleen; trace quantities (<1.0 mg%) were found in the kidney, liver, blood, lung, muscle, and testes. In constrast, in another rat study, ingestion of tungsten resulted in 40% of the dose being excreted in the urine after 24 hours, about 58% being excreted in the feces or remaining unabsorbed in the gut, and 2% remaining in tissues (Friberg, 1979; cited by HSDB, 2016). When given a weak acidic aqueous solution of tungsten trioxide, absorption was 25% in the animals (Aamodt, 1975).

In dogs and rats orally administered a solution of sodium tungstate (25 or 50 mg/kg [0.085 or 0.17 mmol/kg]), absorption of tungsten occurred between one and two hours. In beagle dogs, uptake of tungsten was from 57 to 74% (Le Lamer et al., 2000). As in dogs, absorption in rats was 40 to 92% when tungsten was administered as tungstate and only 1% when administered as tungstic acid (Ballou, 1960; Fleshman et al., 1966; Kaye, 1968; Le Lamer et al., 2000).

McDonald et al. (2007) subjected rats and mice to a single exposure of sodium tungstate at 1, 10, or 100 mg/kg by oral gavage, or by intravenous administration of 1 mg/kg. Plasma and tissue (liver, kidney, uterus, femur, and intestine) were collected at 1, 2, 4, or 24 h after exposure. The results showed tungsten in plasma and all tissues after both gavage and intravenous administration.

There is clearly potential for oral update of the substance. Uptake via inhalation for tungstosilicic acid is not expected as the particle size is insufficiently small for respiratory uptake. As a water soluble inorganic and large molecule, dermal uptake would not be expected.

 

Distribution and Retention:

In vivo experiments using various species, routes of administrations, and compounds showed that a majority of the administered tungsten is rapidly removed from blood (Lagarde and Leroy, 2002). Ingestion of tungsten generally produced higher tungsten levels in the liver compared to other soft tissues, which may be explained by the ability of tungsten to replace molybdenum in certain liver enzymes (e.g., see Aamodt, 1975; Ekman et al., 1977; Ando et al., 1989).

When male and pregnant female mice were injected with tungstate, an increase in tungsten levels was found in the skeleton, kidneys, liver, and spleen. High concentrations were also detected in the thyroid, adrenal medulla, pituitary, and seminal vesicles of males and in the follicules of ovaries in females. Transfer of tungsten from mother to foetus, particularly in late gestation, was observed. Significant retention of the compound was found in the maternal skeleton, kidneys, and spleen and in the visceral yolk sac epithelium and skeleton of the fetus (Wide et al., 1986).

In guinea pigs orally or subcutaneously (s.c.) given sodium tungstate (500 mg [1.70 mmol]), tungsten was detected in the blood and urine, as well as the liver, kidneys, lungs, stomach, and intestines. The lungs and kidneys had maximal radioactivity, whereas other tissues contained only about 10% of the administered dose. Total body burdens of radioactivity were 37% in the skeleton, 31% in lungs, 15% in kidneys, 9.7% in liver, and 5.7% in skeletal muscle (Karantassis, 1924).

An in vitro study showed that tungstate ions bind human albumin and other unknown protein (MW 300 kDa) (Rodriguez-Farinas, 2008). This finding was confirmed in rats, where approximately 80% of serum tungsten was bound to proteins, and most of the protein-bound tungsten was due to a complex with albumin, which is not highly stable. No binding to transferrin was detected. An unknown protein with a molecular weight 100 kDa was also found to bind a small amount of tungsten (approximately 2%). The interaction between reduced glutathione (GSH) and tungstate was also evaluated; however, the formation of complexes was not observed (Gomez-Gomez, 2011).

Ang et al. (2013) investigated the uptake and speciation of tungsten in bones from adult and newborn mice exposed to WO 4 2 _ at levels up to 200 mg/kg/d for 120 d via drinking water. The results suggested that exposure to tungsten results in increased bone mineralization and a resultant increase in bone strength. Whether this is due to the chemical speciation of tungsten or the lteration of cellular processes, was unclear.

Weber et al. (2008) repeatedly exposed rats and mice to sodium tungstate by gavage (10 mg/d) or drinking water (560 mg/L; estimated to be 85 mg/kg/d for rats and 148 mg/kg/d for mice) for 14 consecutive days. Plasma and tissue (intestine, liver, kidney, femur, uterus, and fetus) were collected at 1, 2, 4, or 24 h after exposure. Tungsten was detectable in plasma and all tissues and fetuses of both rats and mice. Accumulation occurred in the intestine, kidney, and femur, with urine being the primary route of elimination. Tungstate may be deposited in bone, by displacing phosphate.

Guandalini et al. (2011) exposed mice to sodium tungstate at 0, 62.5, 125, and 200 mg/kg/d for 28 d, and after 1 d, the tissues of the kidney, liver, colon, bone, brain, and spleen were collected. The results showed increasing tungsten levels in all organs as exposure dose increased, with the highest concentration found in the bones and the lowest concentration found in brain tissue. Gender differences were seen only in the spleen (higher tungsten levels were found in female mice).

Kelly et al. (2013) exposed mice to tungsten as sodium tungstate in their drinking water, at 15, 200, or 1000 mg/L (oral doses estimated to be in the order of 4, 50, and 250 mg/kg/d), for up to 16 weeks. Tungsten concentration in bone was analysed by inductively coupled plasma mass spectrometry. Exposure resulted in a rapid deposition in the bone following 1 week, and tungsten continued to accumulate thereafter, although at a decreased rate.

Tungstates clear distribute around the body and appear to concentrate in bones and a number of organs. It also appears to be able to cross the placenta but the brain is relatively well protected.

Elimination:

The soft tissues, which accumulate a significant amount of deposited tungsten immediately after entering the blood, eliminate it within a few hours (Lagarde and Leroy, 2002). Injection or oral administration of tungstate is rapidly eliminated via urine or faeces; the former appears to be the major excretion pathway (Lagarde and Leroy, 2002,Wide et al., 1986). In rats and dogs, 80-95% is excreted within 24 hours after administration (Aamodt, 1973, 1975; Ando et al., 1989; Kaye, 1968; Durbin, 1960).In the study by McDonald et al. (2007) described previously, plasma concentrations peaked at 4 h in rats and 1 h in mice, with amounts decreasing significantly by 24 h.

From the data above, it appears that tungstates are rapidly eliminated from the body in the urine and faeces.

Biokinetic modelling

In the International Commission for Radiological Protection (ICRP 1981) Biokinetic Model for Tungsten, described in Keith et al (2005), an oral absorption factor of 0.1 is used for oral uptake of acidic tungsten. In this model, absorbed tungsten is assumed to enter the blood, from which 95% immediately transfers to excreta by unspecified routes, 2.5% transfers to bone mineral, 1% transfers to kidney, 1% transfers to liver, and 0.5% transfers to spleen. Tungsten in bone is removed in excretion with half-times of 4 days (20%), 100 days (10%), and 1,000 days (70%). Tungsten in any other tissue is removed to excretion with half-times of 5 days (70%) and 100 days (30%).

Leggett (1997) developed a compartmental model of the biokinetics of absorbed tungsten in adult humans that can be linked to the ICRP’s gastrointestinal tract model. The model predicts a rapid decline in body burden of tungsten after cessation of exposure; approximately 15% of the burden remains after 1 day, 5% after 1 week, 3% after 1 month, 1.6% after 1 year, and 0.4% after 10 years. The slowest component of the decline represents stores in bone volume; therefore, over time, the fraction of the body burden associated with bone increases to 60% after 1 year and 90% after 4 years. Steady state in soft tissue is predicted after approximately 300–500 days of continuous exposure, whereas, bone continues to accumulate tungsten with chronic exposure.

References

Aamodt, R.L. (1975). [title not provided] Health Phys. 28:733-742. Cited by Lagarde and Leroy (2002) and Langård (2001).

Ando, A., J. Ando, T.K. Hiraki, and K. Hisada. (1989). [title not provided] Nucl. Med. Biol. 16:57-80. Cited by Lagarde and Leroy (2002).

Ang CY , Johnson DR , Seiter JM , Allison PG , Osterburg AR , Babcock GF , Kennedy AJ . (2013) . Effects of tungsten chemical species on biochemical pathways and mineralization in bone. [Online] Available at:http://www.toxicology.org/AI/PUB/Tox/2013Tox.pdf(Abstract 1519). Accessed on 23 May 2014.

Ballou, J.E. (1960). Metabolism of [185]W in the rat. AEC Res. Dev. Rep., HW-64112. Cited by Lagarde and Leroy (2002).

DURBIN PW (1960) Metabolic characteristics within a chemical family. Health Phys. 1960 Feb;2:225-38.

Ekman, L., H.D. Figueiras, B.E.V. Jones, and S. Myamoto. (1977). Metabolism of 181W-labeled sodium tungstate in goats. FOA Rep. C-40070-A3. Cited by Lagarde and Leroy (2002).

Fleshman, D., S. Krokz, and A. Silva. (1966). The metabolism of elements of high atomic number. University of California Radiation Laboratory, 14739, pp. 69-86. Cited by Lagarde and Leroy (2002).

Gomez-Gomez MM , Rodiguez-Farinas N , Canas-Montalvo B , Dominguez J , Guinovart J , Camara-Rica C . (2011) . Biospeciation of tungsten in the serum of diabetic and healthy rats treated with the antidiabetic agent sodium tungstate . Talanta , 84 , 1011 – 18 .

Guandalini GS, Zhang L, Fornero E, Centeno JA , Mokashi VP , Ortiz PA , et al . (2011) . Tissue distribution of tungsten in mice following oral exposure to sodium tungstate. Chem Res Toxicol, 24, 488– 93.

HSDB. 2016. Tungsten, elemental. HSDB No. 5036. Available at Internet address: https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp/~gZhLAh:3. Last revised on April 16, 2009. Last accessed on July 28^th2016.

ICRP. (1981).International Commission for Radiological Protection. Limits for intakes ofradionuclides by workers. Commission of Radiological Protection. ICRP Publication 30, Part 3. New York: Pergamon Press, 93-95. In Keith 2007.

Karantassis, T. (1924). [title not provided] Ann. Med. Leg. 5:44 ff. Cited by Langård (2001).

Kaye, S.V. (1968). [title not provided] Health Phys. 15:399-418. Cited by Lagarde and Leroy (2002).

Keith LS , Moff ett D, Rosemond ZA, Wohlers DW , Agency for Toxic Substances and Disease Registry. (2005) . ATSDR evaluation of health effects of tungsten and relevance to public health. Toxicol In Health ,23 , 347 – 87 .

Kelly ADR , Lemaire M , Young YK , Eustache JH , Guilbert C , Molina MF ,Mann KK . (2013) . In vivo tungsten exposure alters B-cell development and increases DNA damage in murine bone marrow . Toxicol Sci , 131 , 434 – 46

Lagarde, F., and M. Leroy. (2002). Metabolism and toxicity of tungsten in humans and animals. Met. Ions Biol. Syst. 39(Molybdenum and Tungsten):741-759

 

Langård, S. (2001). Chromium, Molybdenum, and Tungsten. Patty's Toxicology. 38. DOI: 10.1002/0471435139.tox038

Le Lamer, S., P. Poucheret, G. Cros, R. Kiesgen de Richter, P.A. Bonnet, and F. Bressolle. (2000). [title not provided] J. Pharmacol. Exp. Ther. 294(2):714-721. Cited by Lagarde and Leroy (2002).

Leggett RW. 1997. A model of the distribution and retention of tungsten in the human body. Sci Total Environ 206:147-165. In Keith 2007.

Lemus R, Venezia CF (2015) An update to the toxicological profi le for water-soluble and sparingly soluble tungsten substances. Crit Rev Toxicol, 2015; 45(5): 388–411.

McDonald JD, Weber WM, Marr R, Kracko D, Khain H, Arimoto R .(2007) . Disposition and clearance of tungsten after single-dose oral and intravenous exposure in rodents . J Toxicol Environ Health A , 70 ,829 – 36 .

 

Rodriguez-Farinas N , Gomez-Gomez MM , Camara-Rica C . (2008) .Study of tungstate-protein interaction in human serum by LC-ICP-MS and MALDI-TOF . Anal Bioanal Chem, 390, 29– 35.

Weber WM , Marr R , Kracko D , Gao Z , McDonald JD , Ui Chearnaigh K . (2008) . Disposition of tungsten in rodents after repeat oral and drinking water exposures . Toxicol Environ Chem , 90 , 445 – 55 .

Wide, M., B.R.G. Danielsson, and L. Dencker. (1986). Distribution of tungstate in pregnant mice and effects on embryonic cellin vitro. Environ. Res. 40:487-498. Cited by Domingo (2002), Lagarde and Leroy (2002), and Langård (2001).

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

0

Absorption rate - inhalation (%):

0