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

Abstract

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 (LD50 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.

Benchmark Dose Approach to DNA and Liver Damage by Chlorpyrifos and Imidacloprid in Male Rats: The Protective Effect of a Clove-Oil-Based Nanoemulsion Loaded with Pomegranate Peel Extract

“…The World Health Organization (WHO) and United Nations Environment Programme (UNEP) report that pesticides pose a major threat to human health through direct or indirect exposure, with more than 26 million people suffering from pesticide poisoning and nearly 220,000 deaths each year [ 63 ]. In addition to the common toxic mechanism, neonicotinoids and organophosphate pesticides promote free radical production and can alter the oxidant–antioxidant balance when exposed to very low levels [ 8 , 40 , 64 ]. The human body has various defense mechanisms to protect against free radical species (FRS)/reactive oxygen species (ROS) damage, including enzymatic and nonenzymatic pathways [ 65 , 66 ].…”

“…Depending on their dose, duration, and mode of action, pesticides can cause various types of liver damage, such as inflammation, necrosis, fibrosis, and tumors. Histopathological studies in laboratory animals can reveal the morphological and cellular changes in liver tissue and the possible mechanisms of pesticide-induced hepatotoxicity [ 40 , 109 ]. In the current study, the control rats showed a normal liver architecture while the livers of the rats receiving low and medium doses of IM or CPF showed mild liver damage with some inflammatory cells, enlarged sinusoids, and condensed nuclei.…”

“…According to OECD guidelines [ 58 ], a modified comet assay was used to evaluate how IM and CPF damaged DNA using hepatocytes by single-cell gel electrophoresis as cited in previous studies [ 40 , 59 ]. After the usual steps of washing, embedding the separated cells in agarose gel on microscope slides, lysing, and conducting the alkali treatment for 20 min, electrophoresis was performed (30 min, 300 mA, 25 V).…”

“…The benchmark dose (BMD) was designed as an alternative for risk evaluations due to the limitations of the no-observed-adverse-effect level (NOAEL) [ 39 , 40 ]. A BMD is a statistically lower confidence limit for a dosage causing a predefined increase in the response rate, such as 0.01 or 0.1.…”

Effect of Fipronil Exposure on Hematological Aspects of Rhesus Monkeys (Macaca mulatta): Risk and Toxicity Assessment in Agro-Workers

“…Before exposure to the FPN inhalation, the animals were relaxed with minimum handling stress with no estimated adverse effect level by the operating and handling approaches adopted as reported in the study. 23 …”