New Presentation: Redox and Cellular Stress in Relation to Consumer Risk Assessments

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Many compounds for which consumer safety risk assessments need to be conducted are not associated with specific toxicity modes of action, but rather exhibit non-specific toxicity leading to cell stress (e.g. oxidative stress, mitochondrial toxicity, ER stress). These can lead to the activation of stress-response pathways which, provided the exposure is sufficiently low, allow cells to adapt to an insult. However, if the exposure level is high enough, the homeostatic mechanisms can be overwhelmed, causing the stress pathways to pass through a so-called tipping point, leading to the development of adverse effects within the cell, organ/tissue and ultimately organism. While there has been a significant increase in the sophistication of non-animal models that allow us to study these stress pathway responses, both computationally and experimentally, developing robust risk assessment approaches based on such models remains a challenge. In particular, there are a number of uncertainties associated with using in vitro cell models to predict human in vivo health outcomes, including identifying the stress pathways of concern, defining a suitable tipping point, and extrapolating from acute to chronic exposures. Using oxidative stress as a primary example and case study compounds (including tert-butylhydroquinone, doxorubicin and troglitazone), we will discuss how a tiered approach, whereby at each tier appropriate models (computational and experimental) are employed to reduce these uncertainties and thereby facilitate decision making.

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