Thousands of tons of neonicotinoids are widely used around the world as broad-spectrum systemic insecticides and veterinary drugs. Researchers originally thought that neonicotinoids exhibited low mammalian toxicity. However, following their widespread use, it became increasingly evident that neonicotinoids could have various toxic effects on vertebrates and invertebrates. The primary focus of this review is to summarize the research progress associated with oxidative stress as a plausible mechanism for neonicotinoid-induced toxicity as well as neonicotinoid metabolism. This review summarizes the research conducted over the past decade into the production of reactive oxygen species, reactive nitrogen species, and oxidative stress as aresult of neonicotinoid treatments, along with their correlation with the toxicity and metabolism of neonicotinoids. The metabolism of neonicotinoids and protection of various compounds against neonicotinoid-induced toxicity based on their antioxidative effects is also discussed. This review sheds new light on the critical roles of oxidative stress in neonicotinoid-induced toxicity to nontarget species.

Mechanism of Neonicotinoid Toxicity: Impact on Oxidative Stress and Metabolism

Background Concern about the effects on health of exposure of combined chemicals present in food, air or water are increasing nowadays. However, mechanism and effects of combined chemical contaminants are still poorly know. Scope and approach This review deals with the variety of routes of these chemicals when enter the human body. The gaol is the development of a mechanism-based and quantitative framework for risk assessment to estimate the impact on human health and prevent exposure to multiple chemicals. Key findings and conclusions It has been shown that new studies should be developed taking into account cumulative effect of these substances and different tiers as external exposition, dietary exposition, lifestyle, age and economic factors. New techniques must also be implemented, mainly “omic” techniques, bioassay systems, mathematical modelling, quantitative structure-activity relationship models, and threshold of toxicological concern to develop databases. In conclusion, several programs should continuously be developed by different health agencies to have a better understanding of the effect of these substances and to develop a unified policy.

State of the art on public risk assessment of combined human exposure to multiple chemical contaminants

Low dose, low risk; very low dose, no real risk. Setting a pragmatic threshold below which concerns become negligible is the purpose of thresholds of toxicological concern (TTC). The idea is that such threshold values do not need to be established for each and every chemical based on experimental data, but that by analyzing the distribution of lowest or no-effect doses of many chemicals, a TTC can be defined - typically using the 5th percentile of this distribution and lowering it by an uncertainty factor of, e.g., 100. In doing so, TTC aims to compare exposure information (dose) with a threshold below which any hazard manifestation is very unlikely to occur. The history and current developments of this concept are reviewed and the application of TTC for different regulated products and their hazards is discussed. TTC lends itself as a pragmatic filter to deprioritize testing needs whenever real-life exposures are much lower than levels where hazard manifestation would be expected, a situation that is called "negligible exposure" in the REACH legislation, though the TTC concept has not been fully incorporated in its implementation (yet). Other areas and regulations - especially in the food sector and for pharmaceutical impurities - are more proactive. Large, curated databases on toxic effects of chemicals provide us with the opportunity to set TTC for many hazards and substance classes and thus offer a precautionary second tier for risk assessments if hazard cannot be excluded. This allows focusing testing efforts better on relevant exposures to chemicals.

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Utilizing relative potency factors (RPF) and threshold of toxicological concern (TTC) concepts to assess hazard and human risk assessment profiles of environmental metabolites: A case study