New Presentation: Mitochondrial toxicity and oxidative stress: Defining the tipping point between adaptive and adverse effects for consumer safety risk assessment

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Within emerging Next Generation Risk Assessment (NGRA) frameworks, oxidative stress and mitochondrial toxicity are included as early key events in several Adverse Outcome Pathways (AOPs). A key challenge is to understand how dose-response information from non-animal approaches to studying cell stress/mitochondrial toxicity can be integrated with consumer exposure information to inform safety risk assessments. To begin to address this, we adopted a tiered approach to exposure-led risk assessment using non-animal methodologies to examine oxidative stress and mitochondrial toxicity. Initially the response of a group of case study chemicals (including doxorubicin, diclofenac, troglitazone, phenoxyethanol, niacinamide and caffeine) was assessed using a panel of HepG2-based, high content imaging assays designed to detect effects on several different cell stress pathways including mitochondrial toxicity and oxidative stress. ‘Tipping points’ were then calculated for each of the dose responses obtained and comparison made to the approximate levels of systemic exposure observed in humans for these chemicals. Defining the appropriate tipping points for such dose responses requires considerably more work to understand the relevance of in vitro effects on cell stress markers to adaptive/adverse responses in vivo. For materials where initial work indicates a potential for mitochondrial toxicity, higher tier investigations may be appropriate. One case study chemical (doxorubicin) was evaluated in a human cardiac cell line (AC16) and ihPS-derived cardiomyocytes using markers of mitochondrial toxicity and oxidative stress and tipping points compared to both measured human systemic levels of doxorubicin in patients undergoing treatment as well as systemic levels predicted from Physiologically Based Kinetic modelling. In silico modelling approaches have also been taken to describe the inter-relationship between the biomarkers of mitochondrial biogenesis and damage induced by doxorubicin in cardiomyocytes Our initial results indicate that a tiered approach to the effects of chemicals on cellular stress pathways can be incorporated into an overall exposure-led framework for NGRA.

View the poster here.

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