Benchmark dose and the adverse effects of exposure to pendimethalin at low dose in female rats.

Pendimethalin (PND) is a dinitroaniline herbicide widely used to control broadleaf and annual grasses. Although the acute oral toxicity of PND is >5 g/kg b.wt. in humans (LD ₅₀ for rats >5000 g/kg b.wt.), it has been classified as a possible human carcinogen. It is still used in agriculture so agricultural workers and their families, as well as consumers, can be exposed to this herbicide. The present study is the first report investigating the dose-response effect using the benchmark dose (BMD) and the adverse effects of exposure to PND at low dose via apoptosis responses linked to the expression of tumour necrosis factor-α (TNF-α), FAS and BAX proteins; oxidative stress; and DNA and liver damage in female rats. The rats were exposed to PND via drinking water at doses equivalent to no-observed-adverse-effect level (NOAEL = 100 mg/kg b.wt.), 200 and 400 mg/kg b.wt. for 28 days. PND caused the overexpression of TNF-α, FAS and BAX; increased the levels of serum liver biomarkers; and increased oxidative stress in the liver and erythrocytes. Furthermore, it induced DNA and liver damage in a dose-dependent manner. The BMD showed that serum alkaline phosphatase (ALP) and total antioxidant capacity (78.4 and 30.1 mg/kg b.wt./day, respectively), lipid peroxidation in liver tissue (30.9 mg/kg b.wt./day), catalase in erythrocytes (14.0 mg/kg b.wt./day) and FAS expression in liver tissue (6.89 mg/kg b.wt./day) were highly sensitive biomarkers of PND toxicity. Our findings suggest the generation of reactive oxygen species as a possible mechanism of PND-induced gene overexpression of tumour necrosis factor-α (TNF-α), FAS and BAX proteins, oxidative stress and DNA and liver damage in female rats.
(© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)