Subchronic Oral Toxicity of Sodium Tungstate in Sprague-Dawley Rats

Abstract

The subchronic toxicity of sodium tungstate dihydrate aqueous solution in male and female Sprague-Dawley rats was evaluated by daily oral gavage of 0, 10, 75, 125, or 200 mg/kg/d for 90 days. Measured parameters included food consumption, body weight measurements, hematology, clinical chemistry, and histopathological changes. There was a significant decrease in food consumption and body weight gain in males at 200 mg/kg/d from days 77 to 90; however, there was no effect in food consumption and body weights in females. There were no changes in the hematological and clinical parameters studied. Histopathological changes were seen in kidney of male and female and epididymis of male rats. Histopathological changes were observed in the kidneys of male and female rats dosed at 125 or 200 mg/k/d consisting of mild to severe cortical tubule basophilia in 2 high-dose groups. Histological changes in epididymides included intraluminal hypospermia with cell debris in the 200 mg/kg/d dosed male rats. Histopathological changes were observed in the glandular stomach including inflammation and metaplasia in the high-dose groups (125 or 200 mg/kg/d) of both sexes of rats. Based on histopathology effects seen in the kidneys, the lowest observable adverse effect level was 125 mg/kg/d and the no observable adverse effect level was 75 mg/kg/d in both sexes of rats for oral subchronic toxicity.

An update to the toxicological profile for water-soluble and sparingly soluble tungsten substances

“…Statistically significant body weight reduction findings that had been reported in preclinical diabetic studies were also seen by McCain et al (2010) , who exposed male and female rats to ST for 13 weeks. Significant treatment-group differences in mean body weight compared with untreated animals were observed in males (but not in females) between days 70 and 90, from the 10, 75, and 200 mg/kg/d exposure groups.…”

“…As most metals are excreted through renal clearance and by gastrointestinal excretion, the findings of McCain et al (2010) were not unexpected. Within these nephrotoxic effects, WO 4 2− (in addition to MoO 4 2− , selenate, thiosulfate, succinate, and citrate) may also specifically affect sulfate homeostasis by inhibiting the Na + -sulfate co-transporter NaS1 (SLC13A1), which mediates the sulfate (re)absorption across the renal proximal tubule and small intestinal epithelia ( Markovich 2014 ).…”

“…Histopathological examination of the kidneys in both sexes of rats by McCain et al (2010) revealed WO 4 2− treatment-related effects at 125 and 200 mg/kg/d dose groups. Kidney changes ranged from mild to severe regeneration of cortical tubules showing basophilic tubular profile and thickened basement membrane, diagnosed as progressive nephropathy.…”

“…It is noteworthy that none of the preclinical studies that tested WO 4 2− as an anti-diabetic/obesity agent ( Ballester et al 2007 , Peredo et al 2010 , Nocito et al 2012 , Aydemir et al 2012 , Amigó-Correig et al 2012 ) showed any adverse histopathological findings in the kidneys, despite having exposed the animals for a period of 12 weeks ( Ballester et al 2007 ) to similar concentrations (i.e. 100–190 mg/kg/d or higher, in a study by Oliveira et al (2014) , who exposed mice to 500 mg/kg/d for 3 weeks) as those in the study by McCain et al (2010) .…”

“…A common adverse effect observed in oral repeated- exposure studies in male and female rats ( Ballester et al 2007 , McCain et al 2010 ) or in male mice ( Kelly et al 2013 ) that were exposed to WO 4 2− was a decrease in body weight. It was suggested that this could be mediated by the activation of the hypothalamic leptin pathway ( Amigó-Correig et al 2011 , 2012).…”