Giesy, John P2023-11-162023-11-1620232023-102023-11-16October 20https://hdl.handle.net/10388/15246Abstract Herbicides and safeners have been formulated together to help protect crop plants from the injurious effects of herbicides while maintaining the ability of the herbicides to selectively remove targeted weeds. These groups of compounds became important as agriculture increased to sustain the world's ever-increasing population. Selected emerging safeners (SESs), Mefenpyr di-ethyl (MEF) and Cyprosulfamide (CPS) and their co-herbicides (Fenoxaprop-p-ethyl (FEN) and Isoxaflutole (ISO)) used during pre- and post-emergence of cereals and grains were used for this study. The mobility of safeners varied in the environment in relation to their chemical properties, such as octanol-water solubility partition coefficient. Herbicides and safeners have been found in the aquatic environment because they could dissipate from the point of application through leaching, surface runoff, and volatilization. The sorption of safeners such as CPS to soil was found to be governed by soil pH. Hence, their ability to leach varies for soils depending on their acidity/alkalinity. Safeners are classified as inert for regulatory purposes because they mostly act by upregulating detoxifying enzymes. Despite their presence in surface water and their mobility, there is limited or no data regarding their toxicity to non-target organisms in aquatic environments. Thus, the study focused on evaluating and assessing the toxicity of the SESs on non-target organisms such as Daphnia magna-a cladoceran invertebrate, and Zebrafish (D. rerio)- an aquatic vertebrate animal model. Specifically, the primary objectives of this study were to 1) evaluate and further expand our knowledge on the toxicity of selected safeners for which little toxicological knowledge regarding non-target species like daphnids and fish exist; 2) to evaluate these chemicals singly and in a mixture in an in vivo approach that helps to assess acute, sublethal and chronic effects on the selected model aquatic animals; 3) use simulation models of molecular docking to understand further the interaction of SESs and their herbicides with respect to their binding affinity and predict toxicity on receptors such as growth receptor (4XNN)and hatching enzymes (ZHE1). To address the information gap regarding toxicity of selected safeners, in vivo studies and biochemical assays were done to understand possible reactions in the system of the animals after exposure to serial concentrations of SESs in acute and chronic water-borne exposures. Results from the study showed sublethal and lethal effects on both organisms exposed to MEF and FEN singly and mixed at environmentally relevant concentrations. Lower concentrations of these chemicals caused deformities and inhibited hatching rate, while such effects were not observed for CPS and ISO at the same concentrations. MEF was classified as moderate to high-risk level according to ADMET software. On the contrary, CPS had low to moderate risk levels for both D. magna and D. rerio. A biphasic plot indicating a hormetic reaction was obtained for reproduction in D. magna, suggesting that MEF might be an endocrine-disrupting chemical and induce stress. Lower concentrations (< 3 mg/L) of MEF caused deformations and inhibited the hatching rate in D. rerio embryos. Mixture studies showed infra-additive reactions on endpoints, including survival and hatching rate. Biochemical activities showed a downregulation in GST in some of the chemicals and an inhibition in SOD activities, the organism is mounting an antioxidant response to maintain homeostasis. Molecular docking scores suggested that MEF, CPS, ISO and FEN all binds to the studied receptors (growth (4XNN) and hatching (ZHE1)). Therefore, MEF and CPS have potentials to affect the activities of the selected receptors. Likewise, toxicity estimation software (TEST) predicted MEF and FEN to be developmental toxicants, and that FEN was predicted to have mutagenic potential using consensus method to calculate the end point. While MEF was more potent singly, its toxicity was reduced when in a mixture with another toxic compound (FEN), and this is beneficial to the organism. In the same vein, CPS, which has low potency, also suppressed the toxicity of ISO. The key findings from this study were that even if SESs contributed to mitigating the effects of herbicides on the animal models, there are sublethal effects associated with it, and the adverse outcome is still a cause for concern. Also, safeners categorized as inert should be re-evaluated to account for all their toxic potential.  application/pdfenSafeners, Herbicides, ToxicityThesis2023-11-16