New Publication: Identifying and characterizing stress pathways of concern for consumer safety in next-generation risk assessment

Many substances 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. In this work, a cellular stress panel is described, consisting of 36 biomarkers representing mitochondrial toxicity, cell stress and cell health, measured predominantly using high content imaging. To evaluate the panel, data were generated for fourteen compounds at exposures consistent with typical use-case scenarios. These included some compounds that have been shown to cause adverse effects in a proportion of exposed humans and have a toxicological mode-of-action associated with cellular stress (e.g. doxorubicin, troglitazone, diclofenac), and some compounds that are not associated with adverse effects due to cellular stress at human-relevant exposures (e.g. caffeine, niacinamide and phenoxyethanol). For each compound, concentration response data were generated for each biomarker at three timepoints. A Bayesian model was then developed to quantify the evidence for a biological response, and if present, a credibility range for the estimated point of departure (PoD) was determined. For each compound, the PoDs were compared with the plasma Cmax associated with their typical exposure, which indicated a clear differentiation between ‘low’ risk and ‘high’ risk chemical exposure scenarios. The results provided a strong indication that this approach is useful for identifying and characterizing stress pathways of concern for use in next generation risk assessment.

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