Both sexes of F344 rats were gavaged with maximal tolerated doses of
mercuric chloride for periods from 2 wk to up to 2 yr to investigate chronic nephrotoxicity and potential carcinogenicity. The toxicity of
mercuric chloride was excessive after 2 wk of exposure to doses ranging from 1.25 to 20 mg/kg, compromising renal function by selectively destroying cells of the proximal tubules, and eliciting marked elevations in urinary
biomarker enzymes diagnostic for acute
renal tubule necrosis. In the 2-wk studies, urinary
alkaline phosphatase and
aspartate amino-
transferase were most sensitive to renal
mercury toxicity among a panel of six
enzymes, exhibiting twofold increases above controls at the 5.0 mg/kg dose, before changes in the other
enzymes occurred. Urinary
lactate dehydrogenase was the most responsive
enzyme, with up to 11-fold increases in activity above controls. In response to
mercuric chloride exposure of 5.0 mg/kg for 2-6 mo, the greatest and most persistent increases in elevation of urinary
enzyme activities were exhibited by
alkaline phosphatase and gamma-glutamyl
transferase, which increased two-to threefold above controls. At this interval, the maximal severity of the renal lesions in both sexes of rats was graded as minimal to mild. Beyond 6 mo none of the urinary
enzymes measured in this study was adequate as
biomarkers of nephrotoxicity, although the severity of the renal lesions had progressed.
Mercury accumulated in a dose-related fashion primarily in the kidney, and to a lesser extent in the liver. The severity of the renal lesions was increased by continued exposure to
mercuric chloride, as tissue concentrations of
mercury rose in proportion to dose.
Mercuric chloride treatment for 2 yr clearly exacerbated the severity of the spontaneous nephrotoxicity prevalent in aging F344 rats. The excessive mortality that occurred in the male rats was probably due to a combination of these factors. No renal
tumors were detected in rats, possibly because the potential for their development was reduced; however, direct tissue contact with
mercury induced
squamous-cell papillomas of the forestomach in both sexes.