Benchmark Approach to Unravel Fluoride Toxicity: Liver and Kidney Disruptions in Subacutely Exposed Rats

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Abstract
The dose–response relationship for fluoride (F−) exposure remains largely unexplored. Hence, the current study assessed the hepatotoxic and nephrotoxic effects of subacute exposure (28 days) to increasing F− concentrations in Wistar rats via the benchmark dose (BMD5) method. Thirty male rats were assigned to six groups (n = 5): a control group (tap water) along with five groups that received F− via drinking water at increasing concentrations (10, 25, 50, 100, and 150 mg/L). F− toxicity was determined via water intake, weight gain, histological analyses, redox status, and essential element levels. PROASTweb 70.1 software was utilized to investigate the external and internal F− dose–response relationships. Specified major cytoarchitecture damage and superoxide anion (O2·−), total oxidative status (TOS), superoxide dismutase (SOD) activity, total thiol groups (SH), and advanced oxidation protein product (AOPP) level alterations were detected in both sets of tissues. Moreover, F− caused an imbalance in copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn). The most sensitive parameters were O2·− (0.06 mg F−/kg) in the liver and AOPP (6.5 × 10−6 mg F−/L) in the kidneys. These findings contribute to the limited risk assessment of fluorides and highlight the dose-dependent relationship between redox status parameters and bioelements in the liver and kidneys.
Funding Information
  • Ministry of Science, Technological Development, and Innovation of the Republic of Serbia (451-03-33/2026-03/200161)
  • Ministry of Science, Technological Development, and Innovation of the Republic of Serbia (451-03-34/2026-03/200161)
  • Ministry of Science, Technological Development, and Innovation of the Republic of Serbia (451-03-33/2026-03/200017)

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